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Can We Predict Sudden Cardiac Death in Long-term Survivors of Atrial Switch Surgery for Transposition of the Great Arteries? Miriam Wheeler, MBChB, FRACP, Leeanne Grigg, MBBS, FRACP, and Dominica Zentner, MBBS (Hons), FRACP, PhD Cardiology Department, The Royal Melbourne Hospital, Melbourne, Victoria, Australia ABSTRACT
Objective. This study aims to identify predictors of sudden cardiac death (SCD) in patients with transposition of the great arteries (TGA) who have undergone atrial baffle surgery with the Mustard or Senning operation. Background. Patients with TGA and previous atrial baffle surgery are known to be at increased risk of SCD. Despite this, indications for insertion of an implantable cardiac defibrillator for primary prevention have not been established. Methods. Eighty-nine patients with a diagnosis of TGA and previous Mustard or Senning repair were identified. Medical records were reviewed for SCD, aborted SCD, implantation of cardiac defibrillator (ICD), and use of cardiac medications. Clinically significant events (heart failure admissions, documented arrhythmias, and insertion of a pacemaker) were ascertained, and results of echocardiograms were explored. Results. There were five SCDs in our population, and five patients underwent a primary prevention ICD insertion, with no subsequent sustained ventricular arrhythmia or aborted SCD. Patients who suffered SCD had undergone surgery at an older age (median 53 months vs. 14 months) in a slightly earlier era (median year of operation 1971 vs. 1975). Atrial arrhythmias requiring treatment were documented in 100% of the SCD and in 29% of the no SCD patients. Conclusions. Criteria for insertion of primary prevention implantable cardiac defibrillators postatrial baffle surgery remain to be established. In the SCD subgroup, surgery at an older age, earlier era of surgical repair, and history of atrial arrhythmia appear to convey an increased risk of sudden death. Key Words. Transposition of the Great Arteries; Death, Sudden, Cardiac; Defibrillator, Implantable; Congenital Heart Disease; Mustard Repair; Senning Repair
Introduction
T
he atrial baffle procedures revolutionized outcomes in patients born with transposition of the great arteries (TGA), a condition previously uniformly associated with death. The Senning procedure, first performed in 1958, was designed to direct venous return to the contralateral ventricle using an atrial baffle created from the patient’s own atrial septal tissue. The Mustard procedure, first performed in 1963, an alternative to the Senning procedure, uses a pericardial or synthetic baffle to achieve the same rerouting of blood flow through the heart.1 The result is appropriate ejection of oxygenated blood from the heart achieved in these patients by a systemic right ventricle. Congenit Heart Dis. 2014;9:326–332
Longitudinal follow-up of this population has revealed significant morbidity, such as cardiac dysrhythmias,2,3 and mortality4,5 with an increased risk of sudden cardiac death (SCD).6 A number of potential risk factors for SCD have been described in the literature, including atrial arrhythmias,7–10 palpitations, and syncope8 as well as systemic ventricular dysfunction and older age at operation.11 Unlike the population with left ventricular dysfunction in the setting of ischemic or dilated cardiomyopathy, indications for a primary prevention implantable cardiac defibrillator (ICD) have not been clearly established in congenital heart disease. In particular, in the absence of ventricular arrhythmias or syncope, ventricular dysfunction is not currently a recognized criterion for ICD implantation.12,13 This may place these patients at © 2013 Wiley Periodicals, Inc.
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Sudden Cardiac Death in Atrial Baffle Repair a particular disadvantage given the accepted physiological challenge of the morphological right ventricle acting as a systemic ventricle.6 Methods
A retrospective study was carried out at our tertiary referral center for adult congenital heart disease. Ethics approval was obtained through the Royal Melbourne Hospital Human Research Ethics Committee (QA2010120). Patients with TGA who had undergone an atrial baffle procedure were identified from the Adult Congenital Cardiac Disease database. We excluded those whose initial atrial baffle procedure was followed by an arterial switch procedure and those with Eisenmenger’s syndrome (due to a persistent large nonrestrictive ventricular septal defect (VSD) in one and a patent ductus arteriosus in another) in whom the clinical course was likely to be significantly different. This created the population of 89 patients in this study who had undergone a Mustard (n = 59) or Senning repair (n = 25) or an initial Mustard repair with subsequent Senning procedure in the setting of baffle obstruction (n = 5). All patients were over the age of 18 years. We further characterized the population into complex or simple TGA according to the presence of either a VSD or hemodynamically significant ventricular outflow tract obstruction (complex) or the absence of both these lesions (simple). These 89 patients had a median long-term follow-up of 30 years postsurgery. Medical records and our database were searched to determine: cardiac medications, permanent pacemaker insertion, heart failure admissions, and history of syncope as well as ICD insertion and death. Eleven patients were lost from follow-up by our service (which we defined as nonattendance over the prior 3 years). Where patients were no longer followed up through our service, contact was made with their general practitioner whereby the Table 1.
patients’ vital status could be ascertained if they had been reviewed within the past year. All available echocardiograms and reports and Holter monitor reports were reviewed. Patients were classified as having a history of atrial arrhythmia if they had a documented atrial arrhythmia requiring either medical or electrophysiological management. Patients who had documented nonsustained asymptomatic atrial tachyarrhythmias (defined as less than 30 seconds duration) were not included in the atrial arrhythmia group.14 Five patients underwent at least one electrophysiology study due to recurrent, refractory symptomatic atrial arrhythmias despite medical therapy. Right ventricular function was recorded as assessed by echocardiography in the original report. Digital studies, when available, were also reviewed by a single blinded cardiologist (DZ). Where possible, right ventricular size and function was assessed utilizing tissue Doppler imaging and tricuspid annular plane systolic excursion (TAPSE) as recently described by the American Society of Echocardiography Guidelines for Right Ventricular quantification.15
Statistical Analysis Data are described as median (interquartile range). Comparison between groups and correlation between variables were explored using nonparametric tests (Mann–Whitney for comparisons between groups and Spearman’s rho for correlation) with statistical significance denoted as P < .05. Chi-square statistics were used to compare categorical variables. Results
Baseline Demographics Of the 89 patients identified, vital status could be established in 78 patients. Table 1 presents the gender spread of the population, the number with simple or complex TGA (as previously defined), the
Patient Demographics
Variable
Entire Population (89) Number (%)
Lost to Follow-up (11) Number (%)
Female Simple TGA Complex TGA Mustard operation Senning operation Initial Mustard, subsequent Senning Median age at time of operation (m)
41 (46) 67 (75) 22 (25) 59 (66) 25 (28) 5 (6) 14 (8–24.5)
3 (27) 10 (91) 1 (9) 9 (82) 0 (0) 2 (18) 12 (8–18)
TGA, transposition of the great arteries.
Congenit Heart Dis. 2014;9:326–332
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Wheeler et al.
Table 2. Current Status of Patients (Excluding Those Lost to Follow-Up)
Variable Median age at last follow-up (y) History of atrial arrhythmia (n) (%) Permanent pacemaker implantation (n) (%) Medications at last review (n) ACE inhibitor or ARB Beta-blocker Sotalol Amiodarone Hospital admissions for heart failure (n) ≥Moderate RV dysfunction ≥Moderate TR
Result (n = 78) Median (IQR) or Number 33 (29–38) 27 (35) 23 (29) 42 (54%) 15 (19%) 10 (13%) 3 (4%) 9 (12%) 44 (56%) 25 (32%)
Median age in years (y) and interquartile range (IQR) of the 78 patients (not lost to follow-up). RV, right ventricular; TR, tricuspid regurgitation; ACE inhibitor, angiotensinconverting enzyme inhibitor; ARB, angiotensin receptor blocker.
Table 3. Echocardiography Assessment of Right Ventricular Function Variable
Median (IQR)
Color TDI S′ (units) PW TDI S′ (units) TAPSE (cm) RV base (A4C) (cm) RV mid (A4C) (cm) RV length (A4C) (cm)
5 (4–7) 6.5 (5–9) 1.2 (1–1.5) 5.0 (4.6–5.6) 4.6 (4.2–5.3) 7.8 (7.0–8.5)
S′, systolic velocity of the right ventricular free wall assessed using both color tissue Doppler imaging (TDI) and pulse wave (PW) Doppler; TAPSE, tricuspid annular plane systolic excursion of the right ventricle free wall in cm; RV measurements, the size of the right ventricle measured at its base, midportion, and its length in the apical four-chamber (A4C) view.
type of atrial baffle operation performed, and the age at operation. The subgroup of patients lost to follow-up was not statistically different to the entire population with respect to these characteristics.
Current Status The median age of our population is 32 years with a median postoperative follow-up of 30 years. By this stage, a significant proportion of patients have experienced morbidity such as atrial arrhythmias, insertion of a permanent pacemaker insertion, impaired right ventricular function, and are on cardiac medications (Table 2). Right Ventricular Function Digital echocardiography images were available in a subgroup (n = 44) for reanalysis (Table 3). Not all studies had images that allowed recalculation of all the variables presented, but imaging was adequate in the majority of cases. TAPSE results were lower than the normal value established for the right ventricle (RV) in its usual subpulmonic Congenit Heart Dis. 2014;9:326–332
position.15 There are no established normal values for TAPSE for the RV in a systemic position16 though results reported in two articles are similar to those we found.5,17 In all patients, the original clinical echocardiograph report with its assessment of systemic right ventricular function was also noted. Right ventricular systolic function was assessed as being normal in four patients and decreased in 81 patients. No echocardiographic result was available for four of the patients who were lost to follow-up. Of the 81 patients with impaired function, the severity was classified as mild (n = 35), moderate (n = 27), or severe (n = 19). Tricuspid regurgitation severity had a similar spread, being nil to trivial in 11, mild in 50, moderate in 22, and severe in three. Tricuspid regurgitations severity correlated with RV size as might be expected (P = .03). Measurements of RV size were strongly correlated (RV base: correlation with mid-RV width (r = 0.6, P < .001) and length (r = 0.7, P < .001). Functional measures also had strong correlation: RV TAPSE correlated with RV tissue Doppler imaging (systolic waveform) (r = 0.7, P < .001) and with RV free wall pulse wave Doppler (r = 0.65, P < .001).
Atrial Arrhythmias Holter monitor results were available in 78 of our cohort (Table 4). Of these, 37% had experienced atrial arrhythmias as previously defined. Age at operation was statistically different—being older in those patients in our cohort who had atrial arrhythmias documented. These patients were also statistically older at last follow-up, and it is difficult to be certain whether the significant factor is just time postoperation, accepting that our older patients are also those whose initial operation was done at an older age. Death Seven deaths occurred in our population. Of these, five patients were SCD. Of the other two deaths, one was a cardiac complication (endocarditis complicating bioprosthetic mitral and tricuspid valves) and the other was thought to be unrelated (lobar pneumonia). A prior history of syncope was documented in three of the five cases of SCD. In two of the five SCDs, pregnancy may have been a significant factor. In one woman, death occurred during pregnancy, resulting in loss of both mother and baby and in another woman death occurred 6 months
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Sudden Cardiac Death in Atrial Baffle Repair Table 4.
Atrial Arrhythmia Documentation—Patient Characteristics
Variable
Atrial Arrhythmias (n = 29)
No Atrial Arrhythmias (n = 49)
P
Op age (m) Age last review (y) Time post op (y) RV function (≥moderate dysfunction) RV size (cm)
19 (11–42) 36 (31.5–40) 34 (27.5–36) 21 5.5 (5.0–6.2)
12 (5–17.5) 30 (28–37) 30 (28–34.5) 22 5.1 (4.6–5.8)
.006* .013* ns* .02∧ ns*
RV size (cm) using the base of the RV in the apical four-chamber view. Statistical comparison is denoted by P value using parametric comparison (*) for continuous and chi square (∧) for categorical variables.
Table 5.
Comparing the Patients with SCD to the Rest of the Population
Variable
SCD (n = 5)
No SCD (n = 73)
P value
Age at operation (m) Age at last review (y) Tricuspid regurgitation (≥moderate) n (%) RV dysfunction (≥moderate) Atrial arrhythmia Cardiac failure admission (n) ACE inhibitor use (n) Beta-blocker use (n)
53 (21.5–53.5) 29 (25.5–40.5) 5 (100) 3 (60%) 5 (100%) 3 (60%) 3 (60%) 1 (20%)
14 (8–23.5) 33 (29–38) 20 (27) 41 (56%) 22 (30%) 11 (15%) 39 (53%) 14 (19%)
.02* ns* .003∧ ns∧ .004 .04∧ ns∧ ns∧
Median (IQR) for age at operation in months (m) and age at last review in years (y), number (n) of patients. The statistics used were nonparametric comparison (*) for continuous and chi-square (∧) for categorical variables. ACE, angiotensin-converting enzyme; IQR, interquartile range; RV, right ventricular; SCD, sudden cardiac death.
postpartum. Both these women had experienced clinical events prior to death. In the first, investigations were underway, following palpitations and syncope, and in the second, pregnancy had been complicated by arrhythmias and heart failure. In one further patient, the SCD occurred while exercising. Cardiac arrhythmia documentation was available only in one of the five SCDs where the ambulance recorded ventricular fibrillation on attendance.
ICD Five patients underwent ICD insertion. Indications for ICD insertion were often multiple. All patients had at least moderate right ventricular systolic dysfunction (severe in four patients) and dilatation. All patients had previously had at least one admission for cardiac failure. Two patients also had documented nonsustained ventricular tachycardia on Holter monitor or pacemaker interrogation. In four of these five patients, a history of sustained atrial arrhythmias requiring medical therapy was present, and in three patients, eventual AV node ablation was performed following multiple attempts at electrophysiology ablation, with a prior independent requirement for pacemaker implantation for both brady and/or tachyarrhythmias. Atrial arrhythmias in patients who underwent attempt at electrophysiology ablation arose from both systemic and venous atria with multiple different morphologies noted.
Patients with an ICD were followed up within our defibrillator clinic over a median of 4.6 years (1–5.4). During this follow-up period, no appropriate shocks were delivered. However, inappropriate shocks for atrial arrhythmias (n = 2 patients, each having received more than one shock) and nonsustained ventricular tachycardia not requiring therapy (n = 2) were noted on device interrogation.
Characteristics of the SCD Population Looking in more detail at the small subgroup in which SCD occurred, a number of significant differences emerged compared with the rest of the population in whom long-term follow-up details were available. The SCD patients were significantly older at operation (P = .02), a greater number had moderate or severe tricuspid regurgitation (P = .003) and a heart failure admission (P = .04), and all had experienced atrial arrhythmias (P = .004) (Table 5). Two patients had previously undergone dual chamber pacemaker insertion, and one patient had a single lead pacemaker, with no malignant arrhythmias previously recorded. Arrhythmias immediately prior to death were not documented in the deceased patients. The SCD deaths in our cohort occurred between the years 1998 and 2008, with four deaths prior to 2003. Older age at operation did not correlate with more complex anatomy, but rather patients born in an earlier era. Two of the SCD patients were classified as “complex” TGA (one with a Congenit Heart Dis. 2014;9:326–332
330 Table 6.
Wheeler et al. Patient Characteristics—Sudden Cardiac Death (SCD) and Implantable Cardiac Defibrillator (ICD) Recipients
Variable
SCD (n = 5)
ICD (n = 5)
Female (n) Simple TGA (n) Median (IQR) age at operation (m) Mustard operation (n) Senning operation (n) Initial Mustard, subsequent Senning (n) Median (IQR) age at last clinic follow-up (y) Atrial arrhythmia (n) Age at death/ICD insertion Permanent pacemaker implantation (n) Medications at last review (n) ACE inhibitor/ARB Beta-blocker Sotalol Amiodarone Hospital admissions for heart failure (n) RV size (≥moderate dilatation) RV function (≥moderate dysfunction) Tricuspid regurgitation (≥moderate regurgitation)
2 3 53 (21.5–53.5) 4 0 1 29 (25.5–40.5) 5 31 (26–41.5) 3
2 3 9 (8–108.5) 5 0 0 37 (33.5–47.5) 4 33 (30–45) 3
3 1 1 1 3 3 3 5
5 5 1 0 5 5 5 2
Number (n) of patients who are female, have simple TGA, their median (IQR) age at operation in months (m), presence of atrial arrhythmias, type of operation, median (IQR) age at last follow-up, insertion of a permanent pacemaker, medications at last review, hospital admissions for heart failure, at least moderate right ventricular dilatation (RV), at least moderate RV dysfunction and at least moderate tricuspid regurgitation in the SCD and ICD subgroups. TGA, transposition of the great arteries; IQR, interquartile range; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
small residual VSD and one with an initial VSD requiring pulmonary artery banding), this, however, did not seem to delay the initial age at operation, which was 12 months and 31 months, respectively.
Characteristics of the SCD and the ICD Subgroups We compared the subgroup in which SCD occurred to the subgroup of those in whom clinical assessment resulted in placement of an ICD (Table 6). The patients who experienced SCD had an operation at an older age, although this was not statistically significantly different, due to the large spread in ages. The age at SCD or ICD implant was very similar. Discussion
Criteria for primary insertion of an ICD in the congenital population are developing more slowly than in the wider population. Unfortunately, the smaller population at risk and hence the lesser absolute events will make it difficult to obtain trial level evidence in this group. Waiting for trial evidence also has the potential to place the lives of these adults at risk. The congenital heart disease patients are often younger than other populations being considered for ICD insertion, and it is imperative that data continue to be pooled between centers to attempt to identify risk factors to guide clinical decision making in these young adults.18 Congenit Heart Dis. 2014;9:326–332
In this population, TGA patients with an atrial baffle who experienced SCD had been operated on at both an older age and in an earlier era. This raises the possibility of confounders, both in the capacity of the heart to adjust to its postoperative physiology later as well as the possible effect of a surgical learning curve and changes in technique (surgical, anesthetic, and postoperative care). Similar findings have been published with Schwerzmann et al.19 demonstrating increased VT or SCD in patients with a later repair and Oechslin et al.5 publishing worse survival with those operated in an earlier era. Interestingly, poor RV function did not appear to be a predictor of SCD. In view of this, it is important to note that none of the patients with a primary prevention ICD, in whom we had used the criteria of both larger and poorly functioning right ventricles, had an appropriate shock delivered during follow-up. It is also possible that poor RV function did not emerge as a predictor because of the difficulty in assessing the complex right ventricular anatomy on echo. Newer echocardiography techniques15 and other imaging modalities will be of significance to future clinical research in this area. Atrial arrhythmias commonly occurred late after operation, as has been noted previously.6,20–22 What is of particular interest, however, is the co-occurrence of atrial arrhythmias with patients experiencing SCD. Due to the retrospective nature of the study, no information was available on the arrhythmia burden of those that experi-
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Sudden Cardiac Death in Atrial Baffle Repair enced SCD other than documented paroxysmal atrial flutter or fibrillation. A multicenter study of patients with TGA and an atrial baffle repair post a primary or secondary ICD found atrial arrhythmias in 50% (n = 9) of patients who received an appropriate shock. In these patients, the atrial arrhythmia preceded or coexisted with the ventricular arrhythmia.7 Although the occurrence of atrial arrhythmias prior to SCD has been described,7–10 this has not been a universal finding with some authors reporting no link between atrial arrhythmias and SCD in their cohorts.19 The presence of sustained atrial arrhythmias in the wider congenital heart disease population has been shown to be associated with significantly increasing the risk of death.23 Interestingly, a recent article that looked at 378 adults with a range of different congenital heart conditions and atrial arrhythmias (46 had TGA with an atrial baffle) suggested that certain factors allowed risk stratification for death. Death included SCD, heart failure death, other cardiovascular death, and noncardiovascular death including perioperative events.24 On multivariate analysis, the stratifying factors were valvular heart disease (at least moderate stenosis or regurgitation), pulmonary hypertension, single ventricle physiology, and a New York Heart Association functional class 3 or 4. The consequence of pregnancy in females with previous atrial baffle surgery has not been extensively investigated, despite the physiological challenge of pregnancy. We have previously retrospectively analyzed outcomes postpregnancy and found an increased rate of heart failure and SCD in our population.25 Complex TGA20,26 with coexisting VSD or ventricular outflow tract obstruction at birth has also been highlighted as a possible risk for SCD. The small numbers in our study (two of five SCDs were complex TGA) do not allow us to draw any further conclusions regarding this.
Conclusion
Although the arterial switch procedure has now largely replaced atrial baffle surgery for TGA, we are faced with an aging population of patients post-Mustard or Senning repair at risk of SCD. Our data add further weight to the significance of atrial arrhythmias as a marker of poor prognosis and raise the need to consider this within SCD risk stratification. Though the postatrial baffle population will decrease over time, it is likely that lessons learned will apply to other adults with congenital heart disease with a systemic RV such as the hypoplastic left heart syndrome. It is also apparent that mere transcription of what works in the noncongenital heart disease population may not benefit our patients. Author Contributions Dr. Miriam Wheeler obtained ethics approval, assisted with study design, collected data, and drafted and approved the article. Dr. Dominica Zentner performed study design and statistical analysis, critical revision, and final approval of the article. Dr. Leeanne Grigg provided assistance with study design and approval of the article.
Corresponding Author: Miriam Wheeler, MBChB, FRACP, St. Paul’s Hospital, 1081 Burrard Street, Vancouver, British Columbia, Canada V6Z 1Y6. Tel: +61 8 8920 6250; Fax: +61 8 8945 1365; E-mail: [email protected] Disclosures: The authors have reported that they have no relationships relevant to the contents of this article to disclose. No grants or other sources of funding were received in relation to the article. Accepted in final form: September 19, 2013. References
Limitations
This was a retrospective cohort study with an overall low event rate. This limits the statistical significance attributable to events. It is also possible that the SCD rate in this population has been underestimated given that vital status could not be determined in 11 patients. As highlighted earlier, not all available studies were in digital format and thus not all could be reviewed and reassessed using current echocardiography guidelines.
1 Freedom R, Yoo S, Williams WG. The Natural and Modified History of Congenital Heart Disease. Oxford: Blackwell Publishing; 2004. 2 Duster MC, Bink-Boelkens MT, Wampler D, Gillette PC, McNamara DG, Cooley DA. Longterm follow-up of dysrhythmias following the Mustard procedure. Am Heart J. 1985;109:1323– 1326. 3 Gillette PC, Kugler JD, Garson A Jr, Gutgesell HP, Duff DF, McNamara DG. Mechanisms of cardiac arrhythmias after the Mustard operation for transposition of the great arteries. Am J Cardiol. 1980; 45:1225–1230. Congenit Heart Dis. 2014;9:326–332
332 4 Roos-Hesselink JW, Meijboom FJ, Spitaels SE, et al. Decline in ventricular function and clinical condition after Mustard repair for transposition of the great arteries (a prospective study of 22–29 years). Eur Heart J. 2004;25:1264–1270. 5 Oechslin E, Jenni R. 40 years after the first atrial switch procedure in patients with transposition of the great arteries: long-term results in Toronto and Zurich. Thorac Cardiovasc Surg. 2000;48:233–237. 6 Gelatt M, Hamilton RM, McCrindle BW, et al. Arrhythmia and mortality after the Mustard procedure: a 30-year single-center experience. J Am Coll Cardiol. 1997;29:194–201. 7 Khairy P, Harris L, Landzberg MJ, et al. Sudden death and defibrillators in transposition of the great arteries with intra-atrial baffles: a multicenter study. Circ Arrhythm Electrophysiol. 2008;1:250–257. 8 Kammeraad JA, van Deurzen CH, Sreeram N, et al. Predictors of sudden cardiac death after Mustard or Senning repair for transposition of the great arteries. J Am Coll Cardiol. 2004;44:1095–1102. 9 Birnie D, Tometzki A, Curzio J, et al. Outcomes of transposition of the great arteries in the era of atrial inflow correction. Heart. 1998;80:170–173. 10 Garson A Jr, McNamara DG. Sudden death in a pediatric cardiology population, 1958 to 1983: relation to prior arrhythmias. J Am Coll Cardiol. 1985;5 (6 suppl):134B–137B. 11 Piran S, Veldtman G, Siu S, Webb GD, Liu PP. Heart failure and ventricular dysfunction in patients with single or systemic right ventricles. Circulation. 2002;105:1189–1194. 12 Baumgartner H, Bonhoeffer P, De Groot NM, et al. ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J. 2010;31:2915–2957. 13 Zipes DP, Camm AJ, Borggrefe M, et al. ACC/ AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48:e247–e346. 14 Page RL, Wilkinson WE, Clair WK, McCarthy EA, Pritchett EL. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. Circulation. 1994;89:224–227. 15 Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart
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in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23:685–713; quiz 86–8. Epub 2010/07/ 14. Davlouros PA, Niwa K, Webb G, Gatzoulis MA. The right ventricle in congenital heart disease. Heart. 2006;92(suppl 1):i27–i38. Wilson NJ, Neutze JM, Rutland MD, Ramage MC. Transthoracic echocardiography for right ventricular function late after the Mustard operation. Am Heart J. 1996;131:360–367. Berul CI, Van Hare GF, Kertesz NJ, et al. Results of a multicenter retrospective implantable cardioverter-defibrillator registry of pediatric and congenital heart disease patients. J Am Coll Cardiol. 2008;51:1685–1691. Schwerzmann M, Salehian O, Harris L, et al. Ventricular arrhythmias and sudden death in adults after a Mustard operation for transposition of the great arteries. Eur Heart J. 2009;30:1873–1879. Love BA, Mehta D, Fuster VF. Evaluation and management of the adult patient with transposition of the great arteries following atrial-level (Senning or Mustard) repair. Nat Clin Pract Cardiovasc Med. 2008;5:454–467. Gatzoulis MA, Walters J, McLaughlin PR, Merchant N, Webb GD, Liu P. Late arrhythmia in adults with the Mustard procedure for transposition of great arteries: a surrogate marker for right ventricular dysfunction? Heart. 2000;84:409–415. Puley G, Siu S, Connelly M, et al. Arrhythmia and survival in patients >18 years of age after the Mustard procedure for complete transposition of the great arteries. Am J Cardiol. 1999;83:1080–1084. Bouchardy J, Therrien J, Pilote L, et al. Atrial arrhythmias in adults with congenital heart disease. Circulation. 2009;120:1679–1686. Yap SC, Harris L, Chauhan VS, Oechslin EN, Silversides CK. Identifying high risk in adults with congenital heart disease and atrial arrhythmias. Am J Cardiol. 2011;108:723–728. Zentner D, Wheeler M, Grigg L. Does pregnancy contribute to systemic right ventricular dysfunction in adults with an atrial switch operation? Heart Lung Circ. 2012;21:433–438. Lange R, Horer J, Kostolny M, et al. Presence of a ventricular septal defect and the Mustard operation are risk factors for late mortality after the atrial switch operation: thirty years of follow-up in 417 patients at a single center. Circulation. 2006;114: 1905–1913.
Can We Predict Sudden Cardiac Death in Long-term Survivors of Atrial Switch Surgery for Transposition of the Great Arteries? Miriam Wheeler, MBChB, FRACP, Leeanne Grigg, MBBS, FRACP, and Dominica Zentner, MBBS (Hons), FRACP, PhD Cardiology Department, The Royal Melbourne Hospital, Melbourne, Victoria, Australia ABSTRACT
Objective. This study aims to identify predictors of sudden cardiac death (SCD) in patients with transposition of the great arteries (TGA) who have undergone atrial baffle surgery with the Mustard or Senning operation. Background. Patients with TGA and previous atrial baffle surgery are known to be at increased risk of SCD. Despite this, indications for insertion of an implantable cardiac defibrillator for primary prevention have not been established. Methods. Eighty-nine patients with a diagnosis of TGA and previous Mustard or Senning repair were identified. Medical records were reviewed for SCD, aborted SCD, implantation of cardiac defibrillator (ICD), and use of cardiac medications. Clinically significant events (heart failure admissions, documented arrhythmias, and insertion of a pacemaker) were ascertained, and results of echocardiograms were explored. Results. There were five SCDs in our population, and five patients underwent a primary prevention ICD insertion, with no subsequent sustained ventricular arrhythmia or aborted SCD. Patients who suffered SCD had undergone surgery at an older age (median 53 months vs. 14 months) in a slightly earlier era (median year of operation 1971 vs. 1975). Atrial arrhythmias requiring treatment were documented in 100% of the SCD and in 29% of the no SCD patients. Conclusions. Criteria for insertion of primary prevention implantable cardiac defibrillators postatrial baffle surgery remain to be established. In the SCD subgroup, surgery at an older age, earlier era of surgical repair, and history of atrial arrhythmia appear to convey an increased risk of sudden death. Key Words. Transposition of the Great Arteries; Death, Sudden, Cardiac; Defibrillator, Implantable; Congenital Heart Disease; Mustard Repair; Senning Repair
Introduction
T
he atrial baffle procedures revolutionized outcomes in patients born with transposition of the great arteries (TGA), a condition previously uniformly associated with death. The Senning procedure, first performed in 1958, was designed to direct venous return to the contralateral ventricle using an atrial baffle created from the patient’s own atrial septal tissue. The Mustard procedure, first performed in 1963, an alternative to the Senning procedure, uses a pericardial or synthetic baffle to achieve the same rerouting of blood flow through the heart.1 The result is appropriate ejection of oxygenated blood from the heart achieved in these patients by a systemic right ventricle. Congenit Heart Dis. 2014;9:326–332
Longitudinal follow-up of this population has revealed significant morbidity, such as cardiac dysrhythmias,2,3 and mortality4,5 with an increased risk of sudden cardiac death (SCD).6 A number of potential risk factors for SCD have been described in the literature, including atrial arrhythmias,7–10 palpitations, and syncope8 as well as systemic ventricular dysfunction and older age at operation.11 Unlike the population with left ventricular dysfunction in the setting of ischemic or dilated cardiomyopathy, indications for a primary prevention implantable cardiac defibrillator (ICD) have not been clearly established in congenital heart disease. In particular, in the absence of ventricular arrhythmias or syncope, ventricular dysfunction is not currently a recognized criterion for ICD implantation.12,13 This may place these patients at © 2013 Wiley Periodicals, Inc.
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Sudden Cardiac Death in Atrial Baffle Repair a particular disadvantage given the accepted physiological challenge of the morphological right ventricle acting as a systemic ventricle.6 Methods
A retrospective study was carried out at our tertiary referral center for adult congenital heart disease. Ethics approval was obtained through the Royal Melbourne Hospital Human Research Ethics Committee (QA2010120). Patients with TGA who had undergone an atrial baffle procedure were identified from the Adult Congenital Cardiac Disease database. We excluded those whose initial atrial baffle procedure was followed by an arterial switch procedure and those with Eisenmenger’s syndrome (due to a persistent large nonrestrictive ventricular septal defect (VSD) in one and a patent ductus arteriosus in another) in whom the clinical course was likely to be significantly different. This created the population of 89 patients in this study who had undergone a Mustard (n = 59) or Senning repair (n = 25) or an initial Mustard repair with subsequent Senning procedure in the setting of baffle obstruction (n = 5). All patients were over the age of 18 years. We further characterized the population into complex or simple TGA according to the presence of either a VSD or hemodynamically significant ventricular outflow tract obstruction (complex) or the absence of both these lesions (simple). These 89 patients had a median long-term follow-up of 30 years postsurgery. Medical records and our database were searched to determine: cardiac medications, permanent pacemaker insertion, heart failure admissions, and history of syncope as well as ICD insertion and death. Eleven patients were lost from follow-up by our service (which we defined as nonattendance over the prior 3 years). Where patients were no longer followed up through our service, contact was made with their general practitioner whereby the Table 1.
patients’ vital status could be ascertained if they had been reviewed within the past year. All available echocardiograms and reports and Holter monitor reports were reviewed. Patients were classified as having a history of atrial arrhythmia if they had a documented atrial arrhythmia requiring either medical or electrophysiological management. Patients who had documented nonsustained asymptomatic atrial tachyarrhythmias (defined as less than 30 seconds duration) were not included in the atrial arrhythmia group.14 Five patients underwent at least one electrophysiology study due to recurrent, refractory symptomatic atrial arrhythmias despite medical therapy. Right ventricular function was recorded as assessed by echocardiography in the original report. Digital studies, when available, were also reviewed by a single blinded cardiologist (DZ). Where possible, right ventricular size and function was assessed utilizing tissue Doppler imaging and tricuspid annular plane systolic excursion (TAPSE) as recently described by the American Society of Echocardiography Guidelines for Right Ventricular quantification.15
Statistical Analysis Data are described as median (interquartile range). Comparison between groups and correlation between variables were explored using nonparametric tests (Mann–Whitney for comparisons between groups and Spearman’s rho for correlation) with statistical significance denoted as P < .05. Chi-square statistics were used to compare categorical variables. Results
Baseline Demographics Of the 89 patients identified, vital status could be established in 78 patients. Table 1 presents the gender spread of the population, the number with simple or complex TGA (as previously defined), the
Patient Demographics
Variable
Entire Population (89) Number (%)
Lost to Follow-up (11) Number (%)
Female Simple TGA Complex TGA Mustard operation Senning operation Initial Mustard, subsequent Senning Median age at time of operation (m)
41 (46) 67 (75) 22 (25) 59 (66) 25 (28) 5 (6) 14 (8–24.5)
3 (27) 10 (91) 1 (9) 9 (82) 0 (0) 2 (18) 12 (8–18)
TGA, transposition of the great arteries.
Congenit Heart Dis. 2014;9:326–332
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Table 2. Current Status of Patients (Excluding Those Lost to Follow-Up)
Variable Median age at last follow-up (y) History of atrial arrhythmia (n) (%) Permanent pacemaker implantation (n) (%) Medications at last review (n) ACE inhibitor or ARB Beta-blocker Sotalol Amiodarone Hospital admissions for heart failure (n) ≥Moderate RV dysfunction ≥Moderate TR
Result (n = 78) Median (IQR) or Number 33 (29–38) 27 (35) 23 (29) 42 (54%) 15 (19%) 10 (13%) 3 (4%) 9 (12%) 44 (56%) 25 (32%)
Median age in years (y) and interquartile range (IQR) of the 78 patients (not lost to follow-up). RV, right ventricular; TR, tricuspid regurgitation; ACE inhibitor, angiotensinconverting enzyme inhibitor; ARB, angiotensin receptor blocker.
Table 3. Echocardiography Assessment of Right Ventricular Function Variable
Median (IQR)
Color TDI S′ (units) PW TDI S′ (units) TAPSE (cm) RV base (A4C) (cm) RV mid (A4C) (cm) RV length (A4C) (cm)
5 (4–7) 6.5 (5–9) 1.2 (1–1.5) 5.0 (4.6–5.6) 4.6 (4.2–5.3) 7.8 (7.0–8.5)
S′, systolic velocity of the right ventricular free wall assessed using both color tissue Doppler imaging (TDI) and pulse wave (PW) Doppler; TAPSE, tricuspid annular plane systolic excursion of the right ventricle free wall in cm; RV measurements, the size of the right ventricle measured at its base, midportion, and its length in the apical four-chamber (A4C) view.
type of atrial baffle operation performed, and the age at operation. The subgroup of patients lost to follow-up was not statistically different to the entire population with respect to these characteristics.
Current Status The median age of our population is 32 years with a median postoperative follow-up of 30 years. By this stage, a significant proportion of patients have experienced morbidity such as atrial arrhythmias, insertion of a permanent pacemaker insertion, impaired right ventricular function, and are on cardiac medications (Table 2). Right Ventricular Function Digital echocardiography images were available in a subgroup (n = 44) for reanalysis (Table 3). Not all studies had images that allowed recalculation of all the variables presented, but imaging was adequate in the majority of cases. TAPSE results were lower than the normal value established for the right ventricle (RV) in its usual subpulmonic Congenit Heart Dis. 2014;9:326–332
position.15 There are no established normal values for TAPSE for the RV in a systemic position16 though results reported in two articles are similar to those we found.5,17 In all patients, the original clinical echocardiograph report with its assessment of systemic right ventricular function was also noted. Right ventricular systolic function was assessed as being normal in four patients and decreased in 81 patients. No echocardiographic result was available for four of the patients who were lost to follow-up. Of the 81 patients with impaired function, the severity was classified as mild (n = 35), moderate (n = 27), or severe (n = 19). Tricuspid regurgitation severity had a similar spread, being nil to trivial in 11, mild in 50, moderate in 22, and severe in three. Tricuspid regurgitations severity correlated with RV size as might be expected (P = .03). Measurements of RV size were strongly correlated (RV base: correlation with mid-RV width (r = 0.6, P < .001) and length (r = 0.7, P < .001). Functional measures also had strong correlation: RV TAPSE correlated with RV tissue Doppler imaging (systolic waveform) (r = 0.7, P < .001) and with RV free wall pulse wave Doppler (r = 0.65, P < .001).
Atrial Arrhythmias Holter monitor results were available in 78 of our cohort (Table 4). Of these, 37% had experienced atrial arrhythmias as previously defined. Age at operation was statistically different—being older in those patients in our cohort who had atrial arrhythmias documented. These patients were also statistically older at last follow-up, and it is difficult to be certain whether the significant factor is just time postoperation, accepting that our older patients are also those whose initial operation was done at an older age. Death Seven deaths occurred in our population. Of these, five patients were SCD. Of the other two deaths, one was a cardiac complication (endocarditis complicating bioprosthetic mitral and tricuspid valves) and the other was thought to be unrelated (lobar pneumonia). A prior history of syncope was documented in three of the five cases of SCD. In two of the five SCDs, pregnancy may have been a significant factor. In one woman, death occurred during pregnancy, resulting in loss of both mother and baby and in another woman death occurred 6 months
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Sudden Cardiac Death in Atrial Baffle Repair Table 4.
Atrial Arrhythmia Documentation—Patient Characteristics
Variable
Atrial Arrhythmias (n = 29)
No Atrial Arrhythmias (n = 49)
P
Op age (m) Age last review (y) Time post op (y) RV function (≥moderate dysfunction) RV size (cm)
19 (11–42) 36 (31.5–40) 34 (27.5–36) 21 5.5 (5.0–6.2)
12 (5–17.5) 30 (28–37) 30 (28–34.5) 22 5.1 (4.6–5.8)
.006* .013* ns* .02∧ ns*
RV size (cm) using the base of the RV in the apical four-chamber view. Statistical comparison is denoted by P value using parametric comparison (*) for continuous and chi square (∧) for categorical variables.
Table 5.
Comparing the Patients with SCD to the Rest of the Population
Variable
SCD (n = 5)
No SCD (n = 73)
P value
Age at operation (m) Age at last review (y) Tricuspid regurgitation (≥moderate) n (%) RV dysfunction (≥moderate) Atrial arrhythmia Cardiac failure admission (n) ACE inhibitor use (n) Beta-blocker use (n)
53 (21.5–53.5) 29 (25.5–40.5) 5 (100) 3 (60%) 5 (100%) 3 (60%) 3 (60%) 1 (20%)
14 (8–23.5) 33 (29–38) 20 (27) 41 (56%) 22 (30%) 11 (15%) 39 (53%) 14 (19%)
.02* ns* .003∧ ns∧ .004 .04∧ ns∧ ns∧
Median (IQR) for age at operation in months (m) and age at last review in years (y), number (n) of patients. The statistics used were nonparametric comparison (*) for continuous and chi-square (∧) for categorical variables. ACE, angiotensin-converting enzyme; IQR, interquartile range; RV, right ventricular; SCD, sudden cardiac death.
postpartum. Both these women had experienced clinical events prior to death. In the first, investigations were underway, following palpitations and syncope, and in the second, pregnancy had been complicated by arrhythmias and heart failure. In one further patient, the SCD occurred while exercising. Cardiac arrhythmia documentation was available only in one of the five SCDs where the ambulance recorded ventricular fibrillation on attendance.
ICD Five patients underwent ICD insertion. Indications for ICD insertion were often multiple. All patients had at least moderate right ventricular systolic dysfunction (severe in four patients) and dilatation. All patients had previously had at least one admission for cardiac failure. Two patients also had documented nonsustained ventricular tachycardia on Holter monitor or pacemaker interrogation. In four of these five patients, a history of sustained atrial arrhythmias requiring medical therapy was present, and in three patients, eventual AV node ablation was performed following multiple attempts at electrophysiology ablation, with a prior independent requirement for pacemaker implantation for both brady and/or tachyarrhythmias. Atrial arrhythmias in patients who underwent attempt at electrophysiology ablation arose from both systemic and venous atria with multiple different morphologies noted.
Patients with an ICD were followed up within our defibrillator clinic over a median of 4.6 years (1–5.4). During this follow-up period, no appropriate shocks were delivered. However, inappropriate shocks for atrial arrhythmias (n = 2 patients, each having received more than one shock) and nonsustained ventricular tachycardia not requiring therapy (n = 2) were noted on device interrogation.
Characteristics of the SCD Population Looking in more detail at the small subgroup in which SCD occurred, a number of significant differences emerged compared with the rest of the population in whom long-term follow-up details were available. The SCD patients were significantly older at operation (P = .02), a greater number had moderate or severe tricuspid regurgitation (P = .003) and a heart failure admission (P = .04), and all had experienced atrial arrhythmias (P = .004) (Table 5). Two patients had previously undergone dual chamber pacemaker insertion, and one patient had a single lead pacemaker, with no malignant arrhythmias previously recorded. Arrhythmias immediately prior to death were not documented in the deceased patients. The SCD deaths in our cohort occurred between the years 1998 and 2008, with four deaths prior to 2003. Older age at operation did not correlate with more complex anatomy, but rather patients born in an earlier era. Two of the SCD patients were classified as “complex” TGA (one with a Congenit Heart Dis. 2014;9:326–332
330 Table 6.
Wheeler et al. Patient Characteristics—Sudden Cardiac Death (SCD) and Implantable Cardiac Defibrillator (ICD) Recipients
Variable
SCD (n = 5)
ICD (n = 5)
Female (n) Simple TGA (n) Median (IQR) age at operation (m) Mustard operation (n) Senning operation (n) Initial Mustard, subsequent Senning (n) Median (IQR) age at last clinic follow-up (y) Atrial arrhythmia (n) Age at death/ICD insertion Permanent pacemaker implantation (n) Medications at last review (n) ACE inhibitor/ARB Beta-blocker Sotalol Amiodarone Hospital admissions for heart failure (n) RV size (≥moderate dilatation) RV function (≥moderate dysfunction) Tricuspid regurgitation (≥moderate regurgitation)
2 3 53 (21.5–53.5) 4 0 1 29 (25.5–40.5) 5 31 (26–41.5) 3
2 3 9 (8–108.5) 5 0 0 37 (33.5–47.5) 4 33 (30–45) 3
3 1 1 1 3 3 3 5
5 5 1 0 5 5 5 2
Number (n) of patients who are female, have simple TGA, their median (IQR) age at operation in months (m), presence of atrial arrhythmias, type of operation, median (IQR) age at last follow-up, insertion of a permanent pacemaker, medications at last review, hospital admissions for heart failure, at least moderate right ventricular dilatation (RV), at least moderate RV dysfunction and at least moderate tricuspid regurgitation in the SCD and ICD subgroups. TGA, transposition of the great arteries; IQR, interquartile range; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
small residual VSD and one with an initial VSD requiring pulmonary artery banding), this, however, did not seem to delay the initial age at operation, which was 12 months and 31 months, respectively.
Characteristics of the SCD and the ICD Subgroups We compared the subgroup in which SCD occurred to the subgroup of those in whom clinical assessment resulted in placement of an ICD (Table 6). The patients who experienced SCD had an operation at an older age, although this was not statistically significantly different, due to the large spread in ages. The age at SCD or ICD implant was very similar. Discussion
Criteria for primary insertion of an ICD in the congenital population are developing more slowly than in the wider population. Unfortunately, the smaller population at risk and hence the lesser absolute events will make it difficult to obtain trial level evidence in this group. Waiting for trial evidence also has the potential to place the lives of these adults at risk. The congenital heart disease patients are often younger than other populations being considered for ICD insertion, and it is imperative that data continue to be pooled between centers to attempt to identify risk factors to guide clinical decision making in these young adults.18 Congenit Heart Dis. 2014;9:326–332
In this population, TGA patients with an atrial baffle who experienced SCD had been operated on at both an older age and in an earlier era. This raises the possibility of confounders, both in the capacity of the heart to adjust to its postoperative physiology later as well as the possible effect of a surgical learning curve and changes in technique (surgical, anesthetic, and postoperative care). Similar findings have been published with Schwerzmann et al.19 demonstrating increased VT or SCD in patients with a later repair and Oechslin et al.5 publishing worse survival with those operated in an earlier era. Interestingly, poor RV function did not appear to be a predictor of SCD. In view of this, it is important to note that none of the patients with a primary prevention ICD, in whom we had used the criteria of both larger and poorly functioning right ventricles, had an appropriate shock delivered during follow-up. It is also possible that poor RV function did not emerge as a predictor because of the difficulty in assessing the complex right ventricular anatomy on echo. Newer echocardiography techniques15 and other imaging modalities will be of significance to future clinical research in this area. Atrial arrhythmias commonly occurred late after operation, as has been noted previously.6,20–22 What is of particular interest, however, is the co-occurrence of atrial arrhythmias with patients experiencing SCD. Due to the retrospective nature of the study, no information was available on the arrhythmia burden of those that experi-
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Sudden Cardiac Death in Atrial Baffle Repair enced SCD other than documented paroxysmal atrial flutter or fibrillation. A multicenter study of patients with TGA and an atrial baffle repair post a primary or secondary ICD found atrial arrhythmias in 50% (n = 9) of patients who received an appropriate shock. In these patients, the atrial arrhythmia preceded or coexisted with the ventricular arrhythmia.7 Although the occurrence of atrial arrhythmias prior to SCD has been described,7–10 this has not been a universal finding with some authors reporting no link between atrial arrhythmias and SCD in their cohorts.19 The presence of sustained atrial arrhythmias in the wider congenital heart disease population has been shown to be associated with significantly increasing the risk of death.23 Interestingly, a recent article that looked at 378 adults with a range of different congenital heart conditions and atrial arrhythmias (46 had TGA with an atrial baffle) suggested that certain factors allowed risk stratification for death. Death included SCD, heart failure death, other cardiovascular death, and noncardiovascular death including perioperative events.24 On multivariate analysis, the stratifying factors were valvular heart disease (at least moderate stenosis or regurgitation), pulmonary hypertension, single ventricle physiology, and a New York Heart Association functional class 3 or 4. The consequence of pregnancy in females with previous atrial baffle surgery has not been extensively investigated, despite the physiological challenge of pregnancy. We have previously retrospectively analyzed outcomes postpregnancy and found an increased rate of heart failure and SCD in our population.25 Complex TGA20,26 with coexisting VSD or ventricular outflow tract obstruction at birth has also been highlighted as a possible risk for SCD. The small numbers in our study (two of five SCDs were complex TGA) do not allow us to draw any further conclusions regarding this.
Conclusion
Although the arterial switch procedure has now largely replaced atrial baffle surgery for TGA, we are faced with an aging population of patients post-Mustard or Senning repair at risk of SCD. Our data add further weight to the significance of atrial arrhythmias as a marker of poor prognosis and raise the need to consider this within SCD risk stratification. Though the postatrial baffle population will decrease over time, it is likely that lessons learned will apply to other adults with congenital heart disease with a systemic RV such as the hypoplastic left heart syndrome. It is also apparent that mere transcription of what works in the noncongenital heart disease population may not benefit our patients. Author Contributions Dr. Miriam Wheeler obtained ethics approval, assisted with study design, collected data, and drafted and approved the article. Dr. Dominica Zentner performed study design and statistical analysis, critical revision, and final approval of the article. Dr. Leeanne Grigg provided assistance with study design and approval of the article.
Corresponding Author: Miriam Wheeler, MBChB, FRACP, St. Paul’s Hospital, 1081 Burrard Street, Vancouver, British Columbia, Canada V6Z 1Y6. Tel: +61 8 8920 6250; Fax: +61 8 8945 1365; E-mail: [email protected] Disclosures: The authors have reported that they have no relationships relevant to the contents of this article to disclose. No grants or other sources of funding were received in relation to the article. Accepted in final form: September 19, 2013. References
Limitations
This was a retrospective cohort study with an overall low event rate. This limits the statistical significance attributable to events. It is also possible that the SCD rate in this population has been underestimated given that vital status could not be determined in 11 patients. As highlighted earlier, not all available studies were in digital format and thus not all could be reviewed and reassessed using current echocardiography guidelines.
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