ORIGINAL ARTICLES: CONGENITAL SURGERY

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Long-Term Outcomes of the Neoaorta After Arterial Switch Operation for Transposition of the Great Arteries Jennifer G. Co-Vu, MD,* Salil Ginde, MD,* Peter J. Bartz, MD, Peter C. Frommelt, MD, James S. Tweddell, MD, and Michael G. Earing, MD Department of Pediatrics, Division of Pediatric Cardiology, and Department of Internal Medicine, Division of Cardiovascular Medicine, and Department of , Medical College of Wisconsin, Milwaukee, Wisconsin

Background. After the arterial switch operation (ASO) score increased at an average rate of 0.08 per year over for transposition of the great arteries (TGA), the native time after ASO. Freedom from neoaortic root dilation at pulmonary root and valve function in the systemic posi- 1, 5, 10, and 15 years after ASO was 84%, 67%, 47%, and tion, and the long-term risk for neoaortic root dilation 32%, respectively. Risk factors for root dilation include -pre ,(0.003 ؍ and valve regurgitation is currently undefined. The aim history of double-outlet right (p and length of ,(0.01 ؍ of this study was to determine the prevalence and pro- vious banding (p Neoaortic valve regurgitation of at .(0.04 ؍ gression of neoaortic root dilation and neoaortic valve follow-up (p regurgitation in patients with TGA repaired with the least moderate degree was present in 14%. Neoaortic root ASO. dilation was a significant risk factor for neoaortic valve Methods. Measurements of the neoaortic annulus, neo- regurgitation (p < 0.0001). No patient required reinter- aortic root at the level of the sinuses of Valsalva, and the vention on the neoaorta or neoaortic valve during degree of neoaortic regurgitation were assessed by serial follow-up. transthoracic echocardiograms on 124 patients with TGA Conclusions. Progressive neoaortic root dilation is com- at a median follow-up of 7.2 years (range, 1 to 23 years) mon in patients with TGA after the ASO. Continued after the ASO at our institution. surveillance of this population is required. Results. Neoaortic root dilation with z scores of 2.5 or (Ann Thorac Surg 2013;95:1654–9) greater was identified in 66%, and the root diameter z © 2013 by The Society of Thoracic Surgeons

ince the arterial switch operation (ASO) was first Dilation of the neoaortic root has been reported in S described by Jatene and colleagues in 1975 [1],ithas more than two-thirds of patients after ASO [6, 7]. The become the surgical procedure of choice for repair of natural history of neoaortic root dilation in this setting is transposition of the great arteries (TGA). Perioperative unclear. Previous studies have demonstrated conflicting mortality has improved in the more recent eras, and data, with reports of the indexed neoaortic root dimen- several case series have described good long-term sur- sions progressively increasing [8, 9], decreasing [10],or vival in patients up to 30 years after the ASO [2–5]. remaining fixed [11] over time. Neoaortic valve regurgi- However, these long-term studies have also revealed tation may also be an important late complication, and important late complications that contribute to late mor- although uncommon, the need for repair or bidity and the need for reoperation. These late compli- replacement has now been reported in several series late cations include coronary artery insufficiency, right ven- after ASO [12–14]. We sought to determine the preva- tricular outflow tract obstruction, and problems with the lence of neoaortic root dilation and neoaortic valve re- native pulmonary root and in the sys- gurgitation in patients with TGA repaired with ASO at temic position functioning as the neoaortic root and the our institution and to determine risk factors for the neoaortic valve, respectively [4–9]. development of these late complications.

Accepted for publication Oct 31, 2012. *Drs Ginde and Co-Vu contributed equally to this article. Patients and Methods

Address correspondence to Dr Earing, 9000 W Wisconsin Ave, MS 713, This study was approved by the Children’s Hospital of Milwaukee, WI 53226; e-mail: [email protected]. Wisconsin Human Research Review Board and was con-

© 2013 by The Society of Thoracic Surgeons 0003-4975/$36.00 Published by Elsevier Inc http://dx.doi.org/10.1016/j.athoracsur.2012.10.081 Ann Thorac Surg CO-VU ET AL 1655 2013;95:1654–9 NEOAORTA AFTER ARTERIAL SWITCH OPERATION

Table 1. Potential Risk Factors for Neoaortic Annulus indicated trivial to mild regurgitation, 4 to 6 mm Dilation, Neoaortic Root Dilation, and Neoaortic indicated moderate regurgitation, and greater than 6 Regurgitation After Arterial Switch Operation mm indicated severe regurgitation. Moderate and se- Demographic variables vere regurgitation were also verified by left ventricular Age at ASO dilatation and presence of diastolic flow reversal in the aortic arch or descending . Body surface area was Sex calculated by using the formula of Haycock and col- Weight leagues [17]. Height Coexisting anatomic lesions Data Outcomes and Risk Factors Ventricular septal defect Echocardiographic measurements of neoaortic root di- Double outlet right ventricle mensions and neoaortic valve regurgitation were ana- CONGENITAL HEART Coarctation of the aorta lyzed throughout the entire follow-up. Significant neo- Coronary artery anatomy aortic root dilation was defined as maximum systolic Left ventricular outflow tract obstruction dimension at sinuses of Valsalva (midsinus level) z score Bicommissural pulmonary valve of 2.5 or higher, and significant neoaortic annulus dila- Prior intervention to ASO tion was defined as a measurement z score of 2.5 or Balloon higher. We chose 2.5 as the cutoff to exclude patients with Coarctation of the aorta repair borderline dilation (z scores of 1.5 to 2.5). Significant Pulmonary artery banding neoaortic valve regurgitation was defined as moderate or Arch reconstruction severe regurgitation. Placement of a Blalock-Taussig shunt Potential risk factors for the development of neoaortic Associated operation with ASO root dilation, annulus dilation, and neoaortic valve regur- Coarctation of the aorta repair gitation were also analyzed (Table 1). Variables that were Subaortic membrane resection evaluated included demographic data, coexisting ana- Left ventricular outflow tract obstruction repair tomic lesions, interventions before ASO, and additional Ventricular septal defect repair operations performed at the time of ASO. Need for reintervention for neoaortic root dilation or neoaortic ASO ϭ arterial switch operation. valve regurgitation, including valve repair or replace- ment, was also evaluated in the patient cohort. ducted in accordance with all human research regulatory Statistical Analysis requirements. Demographic data are described as mean Ϯ standard deviation or median with ranges. The Kaplan-Meier Patients method was used to assess freedom from neoaortic root A total of 247 patients with TGA who underwent ASO at the Children’s Hospital of Wisconsin were identified in the cardiovascular surgical database from January 1984 to Table 2. Patient Demographic and Clinical Characteristics December 2007. Of these patients, 124 had at least one Median available postoperative transthoracic echocardiogram at (range) least 1 year after ASO and were included in the study. Variables or No. (%) Hospital and outpatient records were reviewed to obtain ϭ demographics, describe preoperative anatomy, and iden- Patient characteristics (n 124) tify potential risk factors predictive of progressive neo- Age at time of ASO, months 0.2 (0.1–60) aortic root dilation or neoaortic root regurgitation. Age at last follow-up, years 7.2 (1–23) Female 36 (29) Echocardiographic Measurements Coexisting lesions (n ϭ 74) Retrospective measurements of the neoaortic annulus Ventricular septal defect 36 (49) and root were performed on all available postoperative Nonusual coronary artery pattern 20 (27) transthoracic echocardiograms. Maximum systolic di- Coarctation of the aorta 14 (19) mensions of the neoaortic annulus (measured at the level Double-outlet right ventricle morphology 11 (15) of valve hinge points of the leaflets) and sinuses of Bicommissural pulmonary valve 7 (10) Valsalva (at the midsinus level) were measured from Left ventricular outflow tract obstruction 2 (3) 2-dimensional parasternal long-axis views. Neoaortic an- Previous intervention before ASO (n ϭ 74) nulus and root (sinuses of Valsalva) diameter z scores Balloon atrial septostomy 40 (54) were derived using the data from Children’s Hospital of Coarctation of the aorta repair 12 (16) Boston [15]. The severity of neoaortic valve regurgitation Pulmonary artery banding 11 (15) was graded by assessing the width of the color Doppler Blalock-Taussig shunt 2 (3) jet of regurgitation measured at the level of the valve in parasternal long-axis view [16]. A jet width of 1 to 4 mm ASO ϭ arterial switch operation. 1656 CO-VU ET AL Ann Thorac Surg NEOAORTA AFTER ARTERIAL SWITCH OPERATION 2013;95:1654–9

dilation and neoaortic regurgitation after ASO. The ran- dom coefficient model with linear fit was used to assess neoaortic root dilation and neoaortic annulus dilation

OGNTLHEART CONGENITAL over time. The Cox proportional hazards model was used for multivariate analysis to identify predictors of out- comes. A p value of less than 0.05 was considered statistically significant.

Results Table 2 summarizes the demographic and clinical char- acteristics of the patient cohort. Of the 124 patients included in the study, the median age at the time of ASO was 0.2 months (range, 0.1 to 60 months), and median follow-up was 7.2 years (range, 1 to 23 years). Coexisting anatomic lesions existed in 74 patients (60%). The most common coexisting lesion with TGA was a ventricular Fig 2. Neoaortic root measurement after arterial switch operation septal defect (VSD), occurring in 36 patients (49%). A (ASO) increased over time at a rate of 0.16 cm per year using the random coefficient model with linear fit. nonusual coronary artery pattern was identified in 20 patients (27%), and 14 (19%) had coarctation of the aorta, 11 (15%) had double-outlet right ventricle (DORV), 7 The risk factors identified as predictors of neoaortic (10%) had an abnormal pulmonary valve, and 2 (3%) had root dilation using multivariate analysis were a history of coexisting left ventricular outflow tract obstruction. DORV (p ϭ 0.003), previous PA banding (p ϭ 0.01), and A previous intervention had been done in 74 patients length of follow-up (p ϭ 0.04). Factors that were not (60%) before ASO. The most common intervention before significant were a history of VSD, coarctation, left ven- ASO was balloon atrial septostomy in 40 (54%), and 12 tricular outflow tract obstruction, and age at ASO. (16%) had coarctation repair, 11 (15%) had pulmonary The neoaortic annulus diameter was significantly di- artery (PA) banding, and 2 (3%) had a modified Blalock- lated, with a z score of 2.5 or higher in 67 patients (54%) Taussig shunt. during follow-up. Using the random coefficient model, Significant neoaortic root dilation developed in 88 of the neoaortic annulus absolute diameter increased at a the 124 patients (66%) during follow-up. The probability rate of 0.09 cm per year (Fig 4); however, the neoaortic of being free from a neoaortic root diameter z score of 2.5 annulus z score remained relatively stable, with a rate of or higher at 1, 5, 10, and 15 years after ASO was 84%, 67%, increase of only 0.0002 per year (Fig 5) over time after 47%, and 32%, respectively (Fig 1). Using the random ASO. Risk factors associated with the presence of signif- coefficient model with linear fit, the neoaortic root abso- icant neoaortic annulus dilation include history of VSD lute diameter increased at a rate of 0.16 cm per year (Fig (p ϭ 0.03), history of DORV (p ϭ 0.02), and the presence 2), and the neoaortic root z score increased at a rate of of a dilated neoaortic root (p Ͻ 0.0001). History of PA 0.08 per year (Fig 3) over time after ASO. banding and length of follow-up were not significantly associated with a dilated aortic annulus. At least moderate neoaortic valve regurgitation was present in 17 of the 124 patients (14%). The probability of

Fig 1. Kaplan-Meier analysis shows probability of freedom from neoaortic root dilation (z score Ͼ 2.5) and neoaortic regurgitation (at Fig 3. The neoaortic root z score increased over time after the arte- least moderate regurgitation) after arterial switch operation (ASO). rial switch operation (ASO) at a rate of 0.08 per year. Ann Thorac Surg CO-VU ET AL 1657 2013;95:1654–9 NEOAORTA AFTER ARTERIAL SWITCH OPERATION

size progressively increased at a mean z-score rate of 0.05 per year until 10 years after the operation, after which the root dimensions appeared to stabilize. In this study, the freedom from neoaortic root dilation, defined as z score of 3 or higher, was only 51% by 10 years after the operation. Two studies, by Hourihan and colleagues [6] and McMahon and colleagues [8], also identified pro- gressive neoaortic root dilation after ASO, with no evi- dence of stabilization in the z-score measurements dur- ing intermediate and long-term follow-up. Our study, which represents one of the longest follow-up periods

after ASO to evaluate neoaortic root dilation, also CONGENITAL HEART showed no evidence of stabilization of root dimensions by 15 to 20 years postoperatively. Risk factors we identified by multivariate analysis for the development of a dilated neoaortic annulus and root Fig 4. The neoaortic annulus measurement increased over time after include a history of DORV and previous PA banding. arterial switch operation (ASO) at a rate of 0.09 cm per year using These risk factors were similar to those identified in the the random coefficient model with linear fit. studies discussed above [8, 11]. One theory for the risk of neoaortic root dilation in patients with TGA and VSD or being free from moderate or severe neoaortic valve DORV is that the presence of a subpulmonary VSD may regurgitation was 96% at 1 year, 92% at 5 years, 89% at 10 result in a relatively dilated native pulmonary annulus years, and 75% at 15 years after ASO (Fig 1). By multi- and root even before surgical repair secondary to in- variate analysis, the risk factors identified as predictors of creased blood flow [8]. Another concern is that the larger neoaortic valve regurgitation were neoaortic root dilation native pulmonary root seen in patients with DORV and (p Ͻ 0.0001), history of DORV (p ϭ 0.003), VSD (p ϭ 0.03), TGA could destabilize the junction with the arterial trunk left ventricular outflow tract obstruction (p ϭ 0.007), and after the ASO and closure of the VSD [9]. Previous PA length of follow-up (p ϭ 0.05). At last follow-up, none of banding was also a significant risk factor for the presence the patients in the cohort had required reintervention for of a dilated neoaortic root but was not a significant neoaortic root dilation or neoaortic valve regurgitation. predictor for a dilated neoaortic annulus. Histologic ex- amination of the dilated neoaortic wall in patients with previous PA banding demonstrates fragmentation and Comment shortening of elastin fibers, suggesting that PA banding In this study, we analyzed the fate of the neoaortic root itself may have a role in progressive root dilation in this and neoaortic valve in 124 patients with TGA after setting [18]. surgical repair with the ASO at our institution. We found It is not clear, however, why the annulus diameter z that a high percentage of patients, 66%, had evidence of score remains relatively stable, albeit dilated, overtime, neoaortic root dilation, 54% had neoaortic annulus dila- while the root diameter z score and degree of root tion, and 14% had at least moderate neoaortic valve dilation progresses after the ASO. The risk for the native regurgitation. The neoaortic root and neoaortic annulus pulmonary root to dilate when in the aortic position may absolute diameter both increased over time after ASO. However, the neoaortic annulus diameter z score re- mained relatively stable, with a rate of increase of only 0.0002 per year, suggesting the neoaortic annulus diam- eter increases proportionately with somatic growth. Di- lation of the neoaortic root over time, however, appears to be a progressive process, with an increase in size that is disproportionate to somatic growth. When analyzing the patients as a whole, one may estimate that the z score of the neoaortic root will increase at a mean rate of 0.08 per year that may continue up to at least 15 years after ASO. These findings differ from a previous report by Hutter and colleagues [10], in which the neoaortic sinus z-score measurements of 144 patients after ASO increased dur- ing the first postoperative year and then gradually de- creased. Our findings of progressive neoaortic root dila- tion are similar, however, to three previous studies of patients after ASO. In a study by Schwartz and col- Fig 5. The neoaortic annulus z score increased over time after arte- leagues [11] of 335 patients after ASO, the neoaortic root rial switch operation (ASO) at a rate of 0.0002 per year. 1658 CO-VU ET AL Ann Thorac Surg NEOAORTA AFTER ARTERIAL SWITCH OPERATION 2013;95:1654–9

be a reflection of histologic differences inherent in the after the ASO, but certain techniques may result in a vessel walls of the pulmonary and aortic arteries. In higher risk for dilation or distortion of the neoaortic root normal at birth, there are differences in the struc- over time [5]. Unlike previous studies, however, our

OGNTLHEART CONGENITAL ture of the aortic and pulmonary vessel walls that be- study did not find age, weight at ASO, coronary anatomy, come more evident with increasing age. Smooth muscle or coronary reimplantation technique were risk factors cells and the elastic laminae of the aortic wall and sinuses for neoaortic valve regurgitation or root dilation. are more compactly organized in a longitudinal fashion Fortunately, no patients in our series have thus far compared with the cells and laminae of the pulmonary required reintervention on the neoaorta. The indications artery, which showed distinct fragmentation in a loosely and timing for repair of neoaortic root dilation are not organized, less dense structure [19]. Similar histologic clear. Nevertheless, elective neoaortic root operations changes have been identified in postmortem studies of after ASO have been reported for patients with z scores unoperated-on patients with TGA, where the native of 8 or higher [11]. In addition, no patients in our series pulmonary wall exhibited a downregulation of all required reintervention on the neoaortic valve. This low smooth muscle cell markers over time, including de- incidence of valve repair and replacement mirrors the ␣ creased expression of -smooth muscle actin, SM22, results reported from other large series, where the need and calponin [19]. for reintervention for neoaortic regurgitation ranged Concern has also been raised about the ability of the from 1.4% to 2.4% [11, 12, 25]. pulmonary root to adapt to a systemic pressure load. Despite the overall low incidence, neoaortic valve Pulmonary autografts in the aortic position express in- repair may still account for a significant percentage of all ␤ creased levels of transforming growth factor- and basic reinterventions in patients after ASO. One study re- fibroblastic growth factor, autocrine growth factors that ported that valve repair or replacement for neoaortic are normally not expressed, or are only faintly expressed, insufficiency accounted for 11.6% of all the reoperations in the mature quiescent arterial wall [20]. The presence of after ASO, highlighting the importance of monitoring for these factors suggests active metabolic and growth activ- this complication in patients long-term after the opera- ity in pulmonary autografts and may be responsible for tion [12]. We recommend periodic evaluations of the the dilation observed in this setting. Also supporting this neoaortic root and valve with echocardiograms every 1 to argument is that neoaortic root dilation has been de- 2 years. Patients with limited echocardiographic win- scribed after repair of other congenital heart conditions dows may require computed tomography or magnetic where the pulmonary root is placed in the systemic resonance imaging to assess the neoaorta. position, such as after the [21] and after This study has several limitations. This is a retrospec- palliation for hypoplastic left heart syndrome [22]. tive study over a long period of time, with variable and The significance of neoaortic root dilation after ASO is incomplete follow-up among patients. We were not able unclear. Fortunately, no case reports have been pub- to account for changes in surgical and postoperative lished in the literature to date of neoaortic dissection in management, which might have been important factors this population. However, there is concern that the pres- in the outcomes we analyzed. In addition, postoperative ence of neoaortic root dilation may have important im- echocardiograms were not available on all patients who plications on the long-term function of the neoaortic valve. Progressive root dilation may result in increased had previously undergone ASO at our institution, raising stress and strain on the neoaortic valve leaflets, as well as question of possible selection bias. A single examiner reduced leaflet coaptation [23]. We found that the pres- performed the measurements; however, there may still ence of neoaortic root dilation was a significant predictor be some measurement variability. Patient medications or of the patient having at least moderate neoaortic valve blood pressure may also potentially affect the measure- regurgitation (p Ͻ 0.0001), suggesting an association ments during serial evaluations. exists between neoaortic root dilation and valve insuffi- In conclusion, neoaortic root dilation and neoaortic ciency after the ASO. In addition, the risk for neoaortic valve regurgitation are common complications in pa- valve regurgitation appeared to increase with length of tients with TGA after repair with ASO. Patients with time after the operation, which parallels the risk for DORV morphologies or previous PA banding may be at neoaortic root dilation. higher risk for these complications. The risk for develop- A previous PA band was not identified as a predictor ing these changes in the neoaorta increases with time. for neoaortic insufficiency in this study, although previ- Finally, when neoaortic root dilation is present, the ous studies have found it to be a significant factor, dimensions may progressively enlarge over time. Con- presumably due to distortion of the native pulmonary tinued surveillance of this population is required. valve before ASO [14, 16]. 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