Genetic Syndromes and Outcome After Surgical Repair of Pulmonary Atresia and Ventricular Septal Defect

Genetic Syndromes and Outcome After Surgical Repair of Pulmonary Atresia and Ventricular Septal Defect Meng-Yu Chen, MD, Shuenn-Nan Chiu, MD, PhD, Jou-Kou Wang, MD, PhD, Chun-Wei Lu, MD, Ming-Tai Lin, MD, PhD, Chung-I Chang, MD, Ing-Sh Chiu, MD, PhD, Yih-Sharng Chen, MD, PhD, Shyh-Jye Chen, MD, PhD, and Mei-Hwan Wu, MD, PhD Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital; Department of Pediatrics, National Taiwan University Hospital; Department of Surgery, National Taiwan University Hospital; Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan Background. Genetic syndromes, especially 22q11 deletion (del22q11) syndrome, are common in patients with pulmonary atresia and ventricular septal defect (PA- VSD), but their association with long-term outcomes varies. The purpose of this study was to evaluate the long-term outcome after complete repair of PA-VSD and to determine the impact of genetic syndromes. Methods. We reviewed our experience of 125 patients with PA-VSD who received primary or staged repair between 1978 and 2010. Evaluations for genetic syndromes included clinical features, cytogenetic analysis, and fluorescence in situ hybridization or multiplex ligation-dependent probe amplification. Results. Genetic syndromes were documented in 26 patients (20.8%), including del22q11 in 16 patients, trisomy 21 in 2 patients, and other syndromes in 8 patients. The prevalence of hypoplastic pulmonary arteries was not significantly different between the syndromic and nonsyndromic groups. After 1,069 patient-years of follow-up, 20-year survival was 90% 6% in patients without syndromes and 14% 23% in patients with syndromes (p < 0.01). Multivariate analysis identified the presence of a genetic syndrome as an important risk factor for hospital and late mortality. Subgroup analysis showed that genetic syndromes other than del22q11 were associated with worse outcome. The rate of 10-year freedom from cardiac reintervention after repair was 53% 11%, with hypoplastic pulmonary arteries before repair as a major risk factor (p 0.02). Conclusions. Genetic syndromes significantly affect survival after repair of PA-VSD, whereas genetic syndromes do not represent additional risk for reintervention. Repair is feasible in patients with syndromes, but suboptimal long-term outcome should be addressed when counseling parents. (Ann Thorac Surg 2012;94:1627 34) 2012 by The Society of Thoracic Surgeons Accepted for publication June 26, 2012. Address correspondence to Dr Chiu, Department of Pediatrics, National Taiwan University Hospital, No. 8, Chung-San South Road, Taipei 100, Taiwan; e-mail: michael@ntuh.gov.tw. Pulmonary atresia and ventricular septal defect (PA- VSD) is a complex congenital heart disease characterized by heterogeneous anomalies of pulmonary artery circulation. Management of these patients is complicated. Early primary repair has been applied in patients with well-developed central pulmonary arteries supplied by a ductus arteriosus, analogous to the treatment paradigm for tetralogy of Fallot (TOF). For those with complex pulmonary artery arborization, staged unifocalization of major aortopulmonary collateral arteries (MAPCAs) is often necessary. However there has not yet been a consensus on the long-term fate of the MAPCAs [1 3]. Until recently, long-term survival of these patients into adulthood was achieved with a multistage approach [3 6]. Factors predictive of mortality include young age, low birth weight, dominant collateral circulation, hypoplastic or absent central pulmonary arteries, and genetic syndromes. Despite numbers of reports from different Western surgical teams, there are limited data analyzing the association between genetic syndromes and postoperative outcomes [3, 7, 8]. In the present study conducted in a large Asian cohort, we sought to determine the early and late results of surgical treatment and to identify risk factors, with particular attention to the impact of genetic syndromes. Material and Methods Patients Between December 1978 and August 2010, 125 consecutive patients underwent repair for PA-VSD at National Taiwan University Hospital in Taiwan. The study was approved by our institutional review board. Signed informed consent forms were collected from the patients undergoing genetic study (or their parents if the patients were younger than 18 years). The medical records, sur- 2012 by The Society of Thoracic Surgeons 0003-4975/$36.00 Published by Elsevier Inc http://dx.doi.org/10.1016/j.athoracsur.2012.06.063

1628 CHEN ET AL Ann Thorac Surg PA-VSD AND GENETIC SYNDROME 2012;94:1627 34 gical reports, and survival data from the National Health Database of all patients were retrospectively reviewed. Patients with atrioventricular septal defect, hypoplastic right or left ventricle, and discordant atrioventricular or ventriculoarterial connection were excluded. Evaluation of genetic syndromes included clinical features, cytogenetic analysis for trisomy, and fluorescence in situ hybridization or multiplex ligation-dependent probe amplification for detection of 22q11 deletion (del22q11). Images of preoperative echocardiography, computed tomography, and cardiac catheterization data were reviewed. The anatomic and morphologic characteristics of the pulmonary circulation were classified on the basis of the types recommended by the Society of Thoracic Surgeons (STS) [9]. Pulmonary artery hypoplasia was defined by a Nakata index less than 90 mm 2 /m 2 [6]. Operative Technique Patients had either a primary 1-stage repair or a staged repair depending on the characteristics of the pulmonary vasculature. Twelve patients had a primary repair (3 with MAPCAs and 9 without MAPCAs), and the atresia was located at valve level in 6 patients. The remainder had a staged repair (37 with MAPCAs and 76 without MAPCAs), either with hypoplastic native pulmonary arteries or dominant collateral arteries. Primary repair consisted of VSD closure and establishment of a right ventricular pulmonary artery connection by means of a transannular patch (using either autologous pericardium or Gore-Tex membrane (W.L. Gore & Associates, Inc, Flagstaff, AZ) or a prosthetic conduit. Initial palliation for the patients undergoing staged procedures involved placement of a systemic-topulmonary artery shunt or creation of a right ventricularto-pulmonary artery continuity as with the primary repair. Unifocalization was undertaken when MAPCAs were large enough to permit construction of an anastomosis. The eventual correction in patients undergoing staged procedures was performed when the growth of the central pulmonary arteries was achieved (Nakata index 150 mm 2 /m 2 ) and no sizable MAPCAs remained. Statistical Analysis SPSS software for Windows, version 15.0 (SPSS Inc, Chicago, IL) was used for data analysis. Data are described as frequency, medians with ranges, or means with standard deviation, as appropriate. Relationships of factors to perioperative or postoperative death were evaluated with Fisher s exact test, the 2 test, Wilcoxon rank sum test, or Student s t test. Survival probabilities were computed with the Kaplan-Meier method, with significance determined by log-rank analysis. Logistic regression and Cox proportional hazard models were applied for regression analysis. Significance was defined as a p value less than 0.05. Results Patient Characteristics Genetic syndromes were diagnosed in 26 patients (20.8%), with del22q11 diagnosed in 16 (12.8%) patients. Additional genetic syndromes included trisomy 21 in 2 patients, VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) in 3 patients, and other syndromes in 5 patients. Twenty-three patients (18.4%) had associated major noncardiac anomalies, and 16 of them were patients with syndromes. Table 1 shows the demographic and anatomic details, as well as surgical strate- Table 1. Demographic, Anatomic, and Operative Details in Patients With Pulmonary Atresia and Ventricular Septal Defect Undergoing Repair Patient Characteristics and Operative Details Total (n 125) No Syndrome (n 99) Syndrome (n 26) p Value Male sex 66 (52.8%) 52 (52.5%) 14 (53.8%) 0.90 Age at repair (mo) 47.4 (0.3 447.9) 47.6 (0.3 447.9) 41.2 (0.7 171.2) 0.64 Body weight at repair (kg) 13.0 (2.2 68.0) 13.0 (2.2 68.0) 10.5 (3.0 38.5) 0.24 Hypoplastic pulmonary arteries a 33 (26.4%) 23 (23.2%) 10 (38.5%) 0.12 STS type b A 85 (68.0%) 70 (70.7%) 15 (57.7%) 0.21 B 40 (32.0%) 29 (29.3%) c 11 (42.3%)... Operative strategy Primary repair 12 (9.6%) 9 (9.1%) 3 (11.5%) 0.71 d Staged repair 113 (90.4%) 90 (90.9%) 23 (88.5%)... Repair method Patch 84 (67.2%) 66 (66.7%) 18 (69.2%) 0.80 Conduit 41 (32.8%) 33 (33.3%) 8 (30.8%)... a Hypoplastic pulmonary arteries refer to Nakata index 90 mm 2 /m 2 ; b STS type: A the presence of native central pulmonary arteries without collateral arteries and B the presence of native central pulmonary arteries and collateral arteries; c five patients with small systemic collaterals; d statistical testing with the Fisher s exact test. Data are given as median (range) or number (%). STS Society of Thoracic Surgeons.

Ann Thorac Surg CHEN ET AL 2012;94:1627 34 PA-VSD AND GENETIC SYNDROME 1629 Table 2. Intraoperative Variables and Early Postoperative Complications Variable Total (n 125) No Syndrome (n 99) Syndrome (n 26) p Value Mean cardiopulmonary bypass time (min) 161.5 53.5 161.8 56.4 106.3 40.7 0.91 Mean cross-clamp time (min) 121.4 40.0 123.9 43.5 112.67 22.6 0.26 Delayed sternal closure 26 (22.4%) 17 (18.9%) 9 (34.6%) 0.03 Arrhythmia (JET, third-degree 3 (2.6%) 3 (3.3%) 0 (0%) 1.00 a atrioventricular block) Residual VSD 13 (10.4%) 9 (9.1%) 4 (15.4%) 0.47 a Mechanical ventilation 96 h 40 (34.5%) 30 (32.3%) 10 (43.5%) 0.31 Pleural effusion 14 d 19 (17.0%) 15 (16.9%) 4 (17.4%) 1.00 a Neurologic complications 11 (9.8%) 7 (7.9%) 4 (17.4%) 0.23 a Sepsis 4 (3.6%) 3 (3.4%) 1 (4.3%) 1.00 a Dialysis 14 (12.5%) 10 (11.2%) 4 (17.4%) 0.48 a Hospital mortality 12 (9.6%) 6 (6.1%) 6 (23.1%) 0.02 a a Statistical testing with Fisher s exact test. Data are given as mean SD, or number (%). JET junctional ectopic tachycardia; VSD ventricular septal defect. gies for syndromic versus nonsyndromic PA-VSD. The median preoperative Nakata index of pulmonary arteries for the entire cohort was 131 mm 2 /m 2 (range, 15.7 640 mm 2 /m 2 ). The prevalence of hypoplastic central pulmonary arteries was higher in patients with syndromes than in patients without syndromes, although this was not statistically different (p 0. 12). Forty (32.0%) patients had MAPCAs, and the median number of MAPCAs was 3 (range, 1 5). None of our patients receiving repair was categorized as STS type C (complete absence of central pulmonary arteries and all of the pulmonary blood supply arising from collateral arteries). STS type B (the presence of central pulmonary arteries and MAPCAs) was more common in patients with syndromes, but the difference between the 2 groups did not reach significance (p 0.21). The types of surgical techniques for repair did not differ between patients with syndromes and those without syndromes (Table 1). Transannular patch for outflow tract reconstruction, however, was strongly associated with a more recent era of operation, with 84% (n 61) occurring in 2001 to 2010, compared with 50% (n 18) in 1990 to 1999, and 31% (n 5) before 1990 (p 0.01). Intracardiac repair was performed concomitant with additional surgical procedures in 37 patients (29.6%), including pulmonary artery plasty in 27 patients and ligation of systemic-to-pulmonary collaterals in 6 patients. Early Outcomes The data on intraoperative variables and postoperative complications are given in Table 2. There was no significant difference in the occurrence of perioperative morbidity except delayed sternal closure between sydromic and nonsyndromic groups. Nine (7.2%) patients underwent reoperation in the early postoperative period, mostly for residual VSD (n 4). There were 12 (9.6%) hospital deaths (within 30 days after the procedure or before discharge), 6 in the nonsyndromic group and 6 in the syndromic group (p 0.02) (Table 2). The causes of early death are listed in Table 3. In the multivariate logistic regression analysis with factors including age, sex, genetic syndromes, pulmonary artery morphologic features, operative methods, and operation era we found significant hazardous effect of genetic syndromes on perioperative mortality (odds ratio 4.65; 95% confidence interval, 1.36 15.9; p 0.01). Follow-Up The duration of total follow-up was 1,069 patient-years, with a median of 8.9 years (range, 3.8 months 32 years). Twelve (10.6%) of 113 operative survivors died a median of 5.2 years (range, 4.9 months 13.2 years) after repair. The causes of late death are outlined in Table 3; the majority of late deaths had cardiac causes. Six patients died of right heart failure and an additional 3 patients died of sudden death or life-threatening arrhythmia. Right heart failure was defined by integrating clinical symptoms marked by venous engorgement, hepatic enlargement, and pitting edema with echocardiographic or angiographic documentation of poor right ventricular contractility. Ten- and 20-year survival after repair for the entire cohort was 81% 8% and 74% 11%, respectively (Fig 1). Cox regression analyses, either univariate or multivariate, of the previously described factors showed that the presence of genetic syndrome was the most important variable adversely affecting long-term survival (Table 4). Patients with del22q11 also had a higher risk of late mortality. Fig 2 shows survival curves for patients with and patients without genetic syndromes. Patients with syndromes had significantly lower 20-year survival than did patients without syndromes (14% 23% versus 90% 6%; p 0.01). A subgroup analysis was applied in 26 patients with syndromes to elucidate the impact of different types of genetic syndromes on surgical outcome. The 10-year survival for patients with syndromes other than del22q11 was lower than that for patients with del22q11 (25% 29% versus 67% 24%; p 0.06) (Fig 2).

Table 3. Patient Characteristics and Causes of Death Patient Genetic Syndromes Pulmonary Artery Morphologic Type (STS) Operative Strategy Repair Method Age at Repair (y) Interval from Repair to Mortality (mo/y) Reoperation in Perioperative or Postoperative Period Cause of Death Hospital death (12 patients) 1 None A Staged Conduit 1.6 0.1 mo No Low cardiac output with systemic inflammatory response syndrome 2 None A Staged Patch 0.2 1.1 mo No Infundibular perforation after catheter-based pulmonary valvotomy prompted emergent outflow reconstruction; died of multiorgan failure 3 None A Staged Patch 2.9 2.6 mo No Mediastinitis 4 None B Staged Conduit 8.4 0.6 mo No Multiorgan failure due to excessive bleeding after operation 5 None B Staged Conduit 8.9 0.4 mo Yes Acute respiratory distress syndrome due to excessive bleeding after operation 6 None B Staged Patch 8.2 3.9 mo Yes RVF with stenotic pulmonary arteries 7 Del22q11 A Staged Patch 3.9 1.3 mo No Diagnosed with epilepsy; brain injury due to status epilepticus 8 Del22q11 B Staged Patch 0.7 3.8 mo No Sepsis, airway anomaly 9 Del22q11 B Staged Patch 4.5 0.0 mo No RVF 10 Trisomy 21 A Staged Patch 1.0 9.3 mo Yes RVF with pulmonary hypertension, obstructive airway with frequent life-threatening events 11 VACTERL A Staged Patch 0.7 0.9 mo Yes RVF with pulmonary hypertension, sepsis 12 Other syndrome B Staged Patch 4.1 0.8 mo Yes RVF with pulmonary hypertension Late death (12 patients) 1 None A Staged Conduit 6.3 2.9 y No Arrhythmia or sudden cardiac death 2 None A Staged Patch 7.3 8.1 y Yes RVF with stenotic pulmonary arteries 3 None B Staged Patch 3.0 4.1 y Yes Acute myeloid leukemia 4 Del22q11 A Primary Patch 0.5 1.5 y Yes Airway hyperresponsiveness and repeated infection 5 Del22q11 A Staged Conduit 5.7 10.6 y No RVF 6 Del22q11 B Staged Patch 2.4 5.6 y No RVF with pulmonary hypertension 7 Trisomy 21 A Staged Patch 13.6 9.6 y No Arrhythmia or sudden cardiac death 8 VACTERL A Primary Patch 0.1 0.5 y No Cholestatic liver disease 9 VACTERL A Staged Patch 4.6 4.8 y No RVF 10 Other A Staged Conduit 3.8 0.9 y No RVF with stenotic pulmonary arteries 11 Other A Staged Conduit 6.6 11.4 y Yes RVF with stenotic pulmonary arteries and residual VSD 12 Other A Staged Patch 14.1 13.2 y Yes Arrhythmia or sudden cardiac death Del22q11 22q11 deletion; RVF right ventricular failure; STS Society of Thoracic Surgeons; VACTERL vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities; VSD ventricular septal defect. 1630 CHEN ET AL Ann Thorac Surg PA-VSD AND GENETIC SYNDROME 2012;94:1627 34

Ann Thorac Surg CHEN ET AL 2012;94:1627 34 PA-VSD AND GENETIC SYNDROME 1631 Fig 1. Overall survival after repair in 125 patients with pulmonary atresia and ventricular septal defect. There were 24 deaths after repair, 12 deaths in early phase after operation, and 12 deaths in later follow-up. The 10- and 20-year survival rates were 81% and 74%, respectively. Numbers at bottom represent the number of patients followed up at that point. Reintervention During the follow-up period, 43 patients (38.0%) required further reoperation (n 22) or percutaneous interventions (n 32), or both, to relieve residual lesions that appeared as right ventricular outflow tract obstruction (n 19), branch pulmonary artery stenosis (n 16), residual VSD (n 9), severe pulmonary insufficiency (n 5), coiling for MAPCAs (n 5), and permanent pacemaker implantation for atrioventricular block (n 1). The rate of freedom from cardiac reintervention was 74% 9% at 5 years, 53% 11% at 10 years, and 32% 14% at 15 years. Reinterventions were prevalent in both patients with syndromes (8/20 [40.0%]) and patients without syndromes (35/93 [37.6%]) (p 0.84). Multivariate analysis showed that hypoplastic pulmonary arteries before repair were an independent predictor of late cardiovascular reintervention (hazard ratio, 2.13; 95% Table 4. Multivariate Cox Regression Analyses of the Risk Factors for Late Mortality Variable Hazard Ratio 95% CI p Value Age at repair 1.000 0.992 1.009 0.80 Male sex 2.013 0.605 6.697 0.19 Genetic syndromes 18.002 4.822 67.20 0.01 Del22q11 7.877 1.575 39.48 0.01 a Hypoplastic pulmonary 1.104 0.298 4.086 0.90 arteries Presence of MAPCAs 0.518 0.113 2.369 0.29 Staged repair 0.593 0.130 2.710 0.54 Conduit 0.623 0.181 2.141 0.26 a Patients with syndromes other than del22q11 were excluded in the regression model. CI confidence interval; Del22q11 22q11 deletion; MAPCAs major aortopulmonary collateral arteries. Fig 2. Survival after repair stratified by types of genetic syndromes. There was a statistically significant difference among 3 subgroups (p 0.01). The 10-year survival was 90% in patients without syndromes, 67% in patients with 22q11 deletion (del22q11) syndrome, and 25% in patients with other syndromes. The solid line indicates those patients without genetic syndromes; the dashed line, those with del22q11 syndromes; and the dash-dot line, those with genetic syndromes other than del22q11. Numbers at bottom represent the number of patients followed up at that point. confidence interval, 1.2 3.9; p 0.02). The presence of a genetic syndrome showed adverse effects on reintervention-free survival on univariate analysis (hazard ratio, 1.91; p 0.05), but this effect was no longer significant on multivariate analysis (p 0.10). Comment This study reports the outcome of repair in patients with PA-VSD from a large Asian cohort. Long-term survival was comparable to those reported in Western series. Patients with genetic syndromes had a significantly higher mortality rate (both hospital and late mortality) than did patients without genetic syndromes. Patients with hypoplastic pulmonary arteries had an increased risk of late reintervention. Previous reports about late outcome of repair in patients with PA-VSD were limited. Most articles investigated the clinical results of single or staged unifocalization [1 3, 10], whereas a few articles discussed follow-up data of patients who either underwent definite repair or did not [4 7]. The 20-year survival in our cohort was 74% and the 10-year reintervention-free survival was 53%, which were close to those reported in Western series [4]. Compared with the outcome of TOF with pulmonary stenosis in our earlier report [11], the early and long-term survival was significantly lower in patients with an extreme form of TOF. Pulmonary regurgitation, right ventricular dilatation, and repolarization heterogeneity have been identified to be associated with life-threatening arrhythmia and sudden death in patients with TOF [12, 13]. Regarding chronic hypoxia and inevitable pulmonary

1632 CHEN ET AL Ann Thorac Surg PA-VSD AND GENETIC SYNDROME 2012;94:1627 34 regurgitation after repair of PA-VSD, we assume that the risk of subsequent right ventricular dilatation and ventricular arrhythmia is even higher in patients with PA- VSD. Consequently, both early and late survival was unfavorably poorer in patients with PA-VSD than in patients with simple TOF [14]. Genetic syndromes occur in more than 20% of patients with PA-VSD, and 22q11 deletion syndrome is known to be the most frequent genetic defect, especially in patients with MAPCAs [7, 15 19]. The impact of genetic syndromes on long-term survival in PA-VSD is controversial. In several previous studies, del22q11 was found to be a risk factor for mortality and reintervention [3, 7, 18]. However, recently Michielon and colleagues [8] suggested that del22q11 and trisomy 21 do not represent risk factors for mortality after repair of conotruncal anomalies but that other syndromes do. In the present study, although our data supported Michielon and colleagues observation that heterogeneous genetic abnormalities other than del22q11 had a worse outcome, we found that del22q11 remained a risk factor for death. The reason for conflicting data between the report from Michielon and colleagues and ours is not clear, but a difference in study populations may explain the disagreement. In Michielon and colleagues study, when assessing patients with conotruncal defects, TOF with pulmonary stenosis was the largest group and accounted for 68.6% of the total 787 patients, whereas PA-VSD with or without MAPCAs was only 15.4%. Although the presence of genetic syndrome does not affect survival after repair of TOF [11], it is not known whether this finding can be applied to patients with PA-VSD. Unlike Michielon and colleagues and our earlier reports, this study focused on PA-VSD, a subtype with more complex cardiac anatomy than simple TOF. The results of survival analysis substantiate the risk of genetic syndromes on perioperative mortality and worse long-term outcome after repair of PA-VSD. The mechanism by which genetic syndromes affect late mortality has been widely discussed [3, 7, 18, 20 23]. Pulmonary artery hypoplasia; extracardiac lesions; depressed immunologic status with ensuring susceptibility to infections; and associated airway problems can account for the higher risk of mortality. Our series found that in patients with syndromes, right heart failure was the most common cause of late death, and lifethreatening arrhythmia also contributed a little. Besides, patients with genetic syndromes had increased cardiovascular mortality independent of other factors. Because right heart failure often relates to high pulmonary vascular resistance or severe forms of pulmonary artery stenosis, we speculate that genetic syndromes may predispose to pulmonary hypertension as well as hypoplasia of the pulmonary arteries [14]. In fact, our study has shown that patients with syndromes had slightly smaller central pulmonary arteries than did those without. This, together with constitutional pulmonary regurgitation and right ventricular dilatation, may result in a propensity to right heart failure and subsequent cardiac death in patients with syndromes. The risk of late reintervention in our patients with PA-VSD was high even after repair. Revision of the right ventricular outflow tract has been the most common late reoperation, and repeated cardiac catheterization with balloon dilation or stenting of residual pulmonary stenosis has been helpful in reducing pulmonary artery resistance and optimizing the distal pulmonary blood flow. Freedom from reintervention in patients with syndromes was reported to be lower compared with patients without syndromes [8], probably because of hypoplasia of the central pulmonary arteries and more frequent use of palliative procedures. In our series, on multivariate analysis only pulmonary artery hypoplasia correlated with reinterventions, whereas genetic syndromes did not. This observation suggests that integrity of the pulmonary vascular bed is the major contributing factor in reintervention for PA-VSD. However some other explanations exist. First, the result could be related to our almost uniform surgical strategy of staged approach and no difference in proportion of staged repair between the 2 patient subgroups. This was much different in Michielon and colleagues experience [8], in which palliative procedures were more frequent in patients with syndromes. Thus reinterventions in patients without syndromes can be biased by the effect of previous palliative procedures on the pulmonary vascular bed in our study. Second, the use of prosthetic conduits in our cohort is more frequent, which also predisposes to reoperation for conduit change. This retrospective study over a span of 32 years has several limitations. First, the patterns of surgical treatment of PA-VSD were different over the period of study at our institution, and the surgical technique and support might have evolved. Second, not all patients underwent routine screening for del22q11, and the tools for diagnosing genetic syndromes changed over time. Patients in whom the diagnosis of 22q11 deletion syndrome was made previously by clinical features were tested later in life. However some patients died in earlier years, and thus it is not possible to confirm the genetic diagnosis by newly developed methods in these patients. Nevertheless, only 3 patients died before 1995, and in the 61 patients receiving multiplex ligation-dependent probe amplification testing in later eras, our clinical diagnosis of del22q11 syndrome had a sensitivity of 100% and a specificity of 95%. This finding may suggest a high accuracy of our clinical recognition of patients with del22q11, but underrecognition is still possible [24]. Finally, because it is difficult to enroll a large number of patients with PA-VSD after repair, the patients with del22q11 syndrome as well as other syndromes were relatively few. This may decrease the statistical power of our study. However all patients with genetic syndromes had complete follow-up, which ensures the validity of outcome assessment in our study. In summary, we have shown that long-term survival after repair in patients with PA-VSD in an Asian cohort is comparable to that in Western countries. Our results confirm that genetic syndromes are the main risk factor for mortality after repair. We could not suggest that

Ann Thorac Surg CHEN ET AL 2012;94:1627 34 PA-VSD AND GENETIC SYNDROME 1633 definite repair should be tailored to patients without syndromes, but suboptimal long-term outcome after repair in patients with syndromes can be expected and should be addressed when counseling parents. References 1. Reddy VM, McElhinney DB, Amin Z, et al. Early and intermediate outcomes after repair of pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries: experience with 85 patients. Circulation 2000;101:1826 32. 2. d Udekem Y, Alphonso N, Norgaard MA, et al. Pulmonary atresia with ventricular septal defects and major aortopulmonary collateral arteries: unifocalization brings no longterm benefits. J Thorac Cardiovasc Surg 2005;130:1496 502. 3. Carotti A, Albanese SB, Filippelli S, et al. Determinants of outcome after surgical treatment of pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries. J Thorac Cardiovasc Surg 2010;140:1092 103. 4. Cho JM, Puga FJ, Danielson GK, et al. Early and long-term results of the surgical treatment of tetralogy of Fallot with pulmonary atresia, with or without major aortopulmonary collateral arteries. J Thorac Cardiovasc Surg 2002;124:70 81. 5. Amark KM, Karamlou T, O Carroll A, et al. Independent factors associated with mortality, reintervention, and achievement of complete repair in children with pulmonary atresia with ventricular septal defect. J Am Coll Cardiol 2006;47:1448 56. 6. Farouk A, Zahka K, Siwik E, et al. Individualized approach to the surgical treatment of tetralogy of Fallot with pulmonary atresia. Cardiol Young 2009;19:76 85. 7. Mahle WT, Crisalli J, Coleman K, et al. Deletion of chromosome 22q11.2 and outcome in patients with pulmonary atresia and ventricular septal defect. Ann Thorac Surg 2003; 76:567 71. 8. Michielon G, Marino B, Oricchio G, et al. Impact of DEL22q11, trisomy 21, and other genetic syndromes on surgical outcome of conotruncal heart defects. J Thorac Cardiovasc Surg 2009;138:565 70.e2. 9. Tchervenkov CI, Roy N. Congenital Heart Surgery Nomenclature and Database Project: pulmonary atresia ventricular septal defect. Ann Thorac Surg 2000;69:S97 105. 10. Gupta A, Odim J, Levi D, Chang RK, Laks H. Staged repair of pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries: experience with 104 patients. J Thorac Cardiovasc Surg 2003;126:1746 52. 11. Chiu SN, Wang JK, Chen HC, et al. Long-term survival and unnatural deaths of patients with repaired tetralogy of Fallot in an Asian cohort. Circ Cardiovasc Qual Outcomes 2012;5:120 5. 12. Gatzoulis MA, Balaji S, Webber SA, et al. Risk factors for arrhythmia and sudden cardiac death late after repair of tetralogy of Fallot: a multicentre study. Lancet 2000;356: 975 81. 13. Chiu SN, Huang SC, Chang CW, et al. The role of mechanical-electrical interaction in ventricular arrhythmia: evidence from a novel animal model for repaired tetralogy of Fallot. Pediatr Res 2011;70:247 52. 14. Knott-Craig CJ, Elkins RC, Lane MM, Holz J, McCue C, Ward KE. A 26-year experience with surgical management of tetralogy of Fallot: risk analysis for mortality or late reintervention. Ann Thorac Surg 1998;66:506 11. 15. Chessa M, Butera G, Bonhoeffer P, et al. Relation of genotype 22q11 deletion to phenotype of pulmonary vessels in tetralogy of Fallot and pulmonary atresia ventricular septal defect. Heart 1998;79:186 90. 16. Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 1998;32:492 8. 17. Anaclerio S, Marino B, Carotti A, et al. Pulmonary atresia with ventricular septal defect: prevalence of deletion 22q11 in the different anatomic patterns. Ital Heart J 2001;2:384 7. 18. Boudjemline Y, Fermont L, Le Bidois J, Lyonnet S, Sidi D, Bonnet D. Prevalence of 22q11 deletion in fetuses with conotruncal cardiac defects: a 6-year prospective study. J Pediatr 2001;138:520 4. 19. Carotti A, Marino B, Di Donato RM. Influence of chromosome 22q11.2 microdeletion on surgical outcome after treatment of tetralogy of fallot with pulmonary atresia. J Thorac Cardiovasc Surg 2003;126:1666 7. 20. Jedele KB, Michels VV, Puga FJ, Feldt RH. Velo-cardio-facial syndrome associated with ventricular septal defect, pulmonary atresia, and hypoplastic pulmonary arteries. Pediatrics 1992;89:915 9. 21. Ackerman MJ, Wylam ME, Feldt RH, et al. Pulmonary atresia with ventricular septal defect and persistent airway hyperresponsiveness. J Thorac Cardiovasc Surg 2001;122: 169 77. 22. Michielon G, Marino B, Formigari R, et al. Genetic syndromes and outcome after surgical correction of tetralogy of Fallot. Ann Thorac Surg 2006;81:968 75. 23. Carotti A, Digilio MC, Piacentini G, Saffirio C, Di Donato RM, Marino B. Cardiac defects and results of cardiac surgery in 22q11.2 deletion syndrome. Dev Disabil Res Rev 2008;14: 35 42. 24. van Engelen K, Topf A, Keavney BD, et al. 22q11.2 Deletion Syndrome is under-recognised in adult patients with tetralogy of Fallot and pulmonary atresia. Heart 2010;96:621 4. INVITED COMMENTARY A comprehensive assessment for genetic syndromes is now considered an integral part of the care of the children with congenital heart disease. This is especially true for pulmonary atresia and ventricular septal defect (PA-VSD), as genetic syndromes may occur in up to 30% of patients [1]. Many studies have demonstrated that genetic syndromes are important predictors of mortality and other important outcome measures, such as duration of mechanical ventilation or length of hospital stay. In PA-VSD, the literature has reported conflicting results regarding genetic syndromes and the risk of mortality. In some studies, microdeletion of 22q (del22q11) has been directly correlated to pulmonary artery anatomy, whereas other studies have not demonstrated any relationship to pulmonary artery architecture or the presence of multiple aortopulmonary collateral arteries [2,3]. The present study by Chen and colleagues [4] demonstrates a rather profound effect of genetic syndromes including del22q11 on both early and late mortality. The authors speculate that many associated features of genetic syndromes, such as impaired immune function, may contribute to this increase. However, analysis of the cause of death suggests that right heart failure is the most common mechanism of death. This finding would suggest that genetic syndromes have a direct effect on the function of the pulmonary arteries. How might one explain this discrepancy between the pulmonary artery size, which is not obviously different 2012 by The Society of Thoracic Surgeons 0003-4975/$36.00 Published by Elsevier Inc http://dx.doi.org/10.1016/j.athoracsur.2012.07.025