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Provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 47, No. 10, 2006 © 2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2005.12.061 Congenital Disease Regurgitation After Arterial Switch Operation for Transposition of the Great Arteries Incidence, Risk Factors, and Outcome Jean Losay, MD, Anita Touchot, MD, Andre Capderou, MD, PHD, Jean-Dominique Piot, MD, Emre Belli, MD, Claude Planché, MD, PHD, Alain Serraf, MD, PHD Le Plessis-Robinson, France

OBJECTIVES The aims of this study were to assess the prevalence and incidence of aortic valve regurgitation (AR) after arterial switch operation (ASO), its outcome, and the risk factors. BACKGROUND After an ASO, the long-term fate of the aortic valve is a concern as follow-up lengthens. METHODS Operative and follow-up data on 1,156 hospital survivors after ASOs between 1982 and December 2000 were reviewed. RESULTS At last follow-up (mean duration 76.2 Ϯ 60.5 months), 172 patients (14.9%) had an AR. Complex transposition of the great arteries, prior pulmonary banding done in 75 patients (21 with intact ventricular septum), aortic arch anomalies, AR at discharge, older age at ASO, and aortic/pulmonary size discrepancy were associated with AR. On multivariate analysis, the presence of a ventricular septal defect (VSD) or AR at discharge multiplied the risk by 2 and 4, respectively. Freedom from AR was 77.9% and 69.5% at 10 and 15 years, respectively; hazard function for AR declined rapidly and slowly increased thereafter. Reoperation from AR was done in 16 patients with one death, valvuloplasty being unsuccessful. Freedom from reoperation for AR was 97.7% and 96.8% at 10 and 15 years, respectively; hazard function slowly increased from 2 to 16 years. Higher late mortality was not associated with AR. CONCLUSIONS After ASO, AR was observed and was related to VSD with attending high pressure and flow and AR at discharge. Progression of AR was slow, but incidence increased with follow-up. Reoperation for AR was rare. Late aortic valve function warrants long-term monitoring. (J Am Coll Cardiol 2006;47:2057–62) © 2006 by the American College of Cardiology Foundation

The arterial switch operation (ASO) has become the surgi- METHODS cal procedure of choice for repair of the transposition of the Patient population. From 1982 to December 2000, 1,265 great arteries (TGA) in neonates and infants (1–4). Yet, children had an ASO; 106 died and 1,159 survived hospi- specific morbidity is observed after ASO, mainly concerning talization (91.6%; 96% confidence interval [CI] 89.9 to the pulmonary outflow tract, the , and the 93.1). Simple TGAs are defined as TGAs with intact ventricular septum and a left (LV)-pulmonary See page 2063 artery (PA) gradient Ͻ50 mm Hg. If a small ventricular septal defect (VSD) (Յ3 mm) was present, it was left by the previous , which has become the aortic valve surgeon. Complex TGAs are TGAs with VSD or Taussig- (5–11). The fate of the new aortic valve is variously assessed Bing anomaly with or without aortic arch obstruction. as the incidence of aortic regurgitation (AR) but seems to Surgical technique. Surgical technique has been described increase as follow-up lengthens (7–17). Aortic regurgitation (4). Surgery was performed in patients on cardiopulmonary incidence and outcome are important to know, as AR can bypass at full flow with a rectal temperature of 25°C. Septal entail severe morbidity such as aortic defect was closed first. The was transected and the (18–20), which can have potential adverse consequences, aortic root fully dissected. A large aortic button containing especially in children. Long-term aortic valve function in a the coronary orifice was taken. The pulmonary trunk was large population who had an ASO at Marie Lannelongue transected, pulmonary branches dissected, and the Lecompte hospital was reviewed to determine the incidence of AR, the maneuver performed. The coronary artery was reimplanted risk factors associated with its occurrence, and its conse- in the appropriate sinus of the PA, in low position for the quences on morbidity and late mortality. left or in high position for the right. reconstruction was done with a fresh autologous pantaloon- shaped pericardial patch. Postoperative evaluation. Since 1985, all survivors had at From the Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France. Manuscript received July 22, 2005; revised manuscript received November 25, least a yearly examination including a clinical assessment, an 2005, accepted December 11, 2005. electrocardiogram, and a two-dimensional echocardiogram 2058 Losay et al. JACC Vol. 47, No. 10, 2006 Aortic Regurgitation After Arterial Switch May 16, 2006:2057–62

evaluate the aortic root Z-score were not undertaken. As Abbreviations and Acronyms most of the patients had a yearly echocardiogram, AR, when AR ϭ aortic regurgitation initially absent, was assumed to appear just before the ASO ϭ arterial switch operation ultrasound examination showing an AR. The evolution of ϭ CI confidence interval the AR increase was evaluated the same way. IVS ϭ intact ventricular septum LV ϭ left ventricle Statistical analysis. Statview 5.0 software (SAS Institute PA ϭ pulmonary artery Inc., Cary, North Carolina) was used for data analysis. PAB ϭ pulmonary artery banding Univariate analysis of continuous variables was performed TGA ϭ transposition of the great arteries with the Student t test. Univariate comparisons for categor- ϭ VSD ventricular septal defect ical variables were performed with the two-tailed chi-square test. Every univariate parameter that reached significance (p Ͻ 0.05) was then tested in a multivariate logistic regres- with color Doppler study done by the referring cardiologist. sion model. Time-related events were examined by the and angiography was done only if actuarial method; analyses were done with censoring of deemed necessary. All these data were regularly transmitted incompletely traced patients after the time of the last to our center, and missing data were completed as thor- follow-up, and differences between groups were calculated oughly as possible by recall of the referring cardiologist. by the log-rank test. The hazard function regression method Follow-up was pursued until June 2004. Overall, three was used to estimate the time-related freedom and hazard patients were immediately lost to follow-up after hospital function of unfavorable outcome (23). discharge. The 1,156 survivors were followed for a mean Ϯ 76.2 60.5 months (median 75 months); follow-up dura- RESULTS tion according to the year of surgery is shown (Fig. 1). Data analysis. The clinical records of all patients were Patients. Preoperative characteristics of the 1,156 hospital reviewed for details of preoperative assessment, operative survivors are presented in Table 1. Most had single TGAs management, and postoperative hospital course. Aortic- in which early referral was the rule; preparatory pulmonary pulmonary size discrepancy was diagnosed when the ob- artery banding (PAB) was done in only 2.6% of patients (21 served pulmonary diameter on aortic diameter ratio was of 815, 95% CI 1.7 to 3.9). Protective PAB was done in above 1.5 on the parasternal short-axis view of the echocar- patients with complex TGA and aortic arch anomalies who diogram and confirmed perioperatively by the surgeon. As had a staged repair in 15.8% (54 of 341) of the cases. Aortic children were followed in different centers all over the arch anomalies were the most frequent associated malfor- country, the presence and quantification of the AR was mations, observed in 98 patients (28.7%) with VSD and 15 locally asserted on the echocardiogram, which was always (1.8%) with intact ventricular septum (IVS). The other most performed by a board-certified pediatric cardiologist. The Table 1. AR quantification was evaluated by color Doppler imaging Preoperative Characteristics of the 1,156 Hospital Survivors and graded as none, trivial, mild, moderate, or severe (0, I to Age (days) at ASO with IV), depending on the ratio of the width of the regurgitant Ϯ jet to the diameter of the high left outflow tract (21); this IVS 13 29 VSD 79.5 Ϯ 252.2 method has been validated before in children (22). The Weight (g) 3,512 Ϯ 1,886 multiplicity of the observers and centers during the TGA (n) with follow-up precluded a measure of interoberserver or in- IVS 815 traobserver variability. For the same reasons, attempts to VSD 269 TB 72 Associated cardiac malformation (n) Aortic arch anomaly 113 Other 179 Coronary patterns (n) I 793 II 34 III 315 IV 8 ND 6 Prior (n) Preparatory PAB (2 stages ASO) 21 Protective PAB 54 PA/Ao size Ն1.5 (n) 123 AR at discharge, I–IV (n) 241 Figure 1. Median follow-up duration according to the year of surgery Ao ϭ aorta; ASO ϭ arterial switch operation; IVS ϭ intact ventricular septum; ND showed in abscissa; the numbers below indicate the number of patients ϭ not determined; PA ϭ pulmonary artery; PAB ϭ pulmonary artery banding; TB operated on during this year. Ordinate is the time from surgery in years. ϭ Taussig-Bing; TGA ϭ transposition of great arteries; VSP ϭ ventricular septal Squares ϭ median value of the follow-up, tips ϭ minimum and maximum. defect. JACC Vol. 47, No. 10, 2006 Losay et al. 2059 May 16, 2006:2057–62 Aortic Regurgitation After Arterial Switch

Table 2. Risk Factors for AR With AR Without AR p Univariate analysis: whole population Complex TGA (%) (TGA with VSD and TB) 25.8 74.2 Ͻ0.0001 TGA with VSD 22.3 77.7 Ͻ0.0001 Associated arch anomaly (%): IIA or CoA 29.2 70.8 Ͻ0.0001 Ao/PA size Ն1.5 (%) 23.6 76.4 Ͻ0.0152 Prior PAB (%) 29.3 70.7 Ͻ0.0003 Age at ASO (day) 66.3 Ϯ 320.6 25.9 Ϯ 68.8 Ͻ0.0005 AR at discharge (%): any grade 34.9 65.1 Ͻ0.0001 Univariate analysis: TGA and IVS Prior PAB (%) 28.0 9.8 0.0053 AR at discharge (%): any grade 23.2 8.3 Ͻ0.0001 Univariate analysis: TGA with VSD Taussig-Bing anomaly 38.9 22.3 0.0043 AR at discharge (%): any grade 45.0 14.2 Ͻ0.0001 Multivariate analysis Complex TGA 1.9 Ͻ0.0014 AR at discharge 4.1 Ͻ0.0001

AR ϭ aortic regurgitation; CoA ϭ coarctation, IIA ϭ interrupted aortic arch; PA ϭ pulmonary artery; other abbreviations as in Table 1. frequent anomalies were multiple VSD (n ϭ 47) and and LV dilation. In one patient with mild AR, mitral and straddling atrioventricular valve (n ϭ 20). An AR was were done at the same time. Isolated observed in 241 patients (20.8%) at discharge and graded as valve replacement was done in nine patients with one early trivial in 214 patients, mild in 25, and moderate in 2. death and one late death. Aortic valve replacement with the Risk factors. At the last follow-up (median follow-up 75 was done in four patients with an impor- months) or just before reoperation for AR, 172 patients tant aortic root dilation. Three other patients had a valvu- (14.9%; 95% CI 13.0% to 17.1%) had an AR; 104 trivial loplasty with one early death and, in another patient, a (9%), 43 mild (3.7%), 19 moderate (1.6%), and 6 severe (0.52%). On univariate analysis, predictors of AR for the whole population were complex TGA, prior PAB, associ- ated coarctation or interrupted aortic arch, pre-ASO aortic/ pulmonary size discrepancy, older age at ASO, and AR at discharge (Table 2). Patients with TGA and VSD, exclud- ing Taussig-Bing anomaly, have more AR. In patients with TGA and IVS, prior PAB and AR at discharge were associated with late AR. In patients with complex TGA, Taussig-Bing anomaly and AR at discharge were associated with a higher incidence of late AR. On multivariate analysis in the whole population, only associated VSD and AR at discharge were significant risk factors, multiplying by 2 and 4 the risk of late AR (Table 2). Time course for outcomes. Freedom from AR was 93.0% at 1 year, 85.2% at 5 years, and 77.9% at 10 years. The hazard function for AR has an initial rapid declining phase followed by a slower decrease and a late slow increase, with new AR observed up to 16 years (Fig. 2). Aortic regurgita- tion evolution according to the AR grade at discharge is shown in Figure 3. Most of the patients without AR at discharge had no AR at last follow-up; only 2.5% had an AR that was mild or worse. Of the 214 patients discharged with a trivial AR, 70% had no AR at the last follow-up and 13% an AR that was mild or worse. In patients with AR that was mild or worse, regurgitation disappeared or de- Figure 2. (A) Actuarial estimate of freedom from aortic regurgitation (AR) creased in 40% of the patients. (grade ՆI) in the 1,156 hospital survivors after the arterial switch operation. Numbers indicate number of patients observed at the beginning Reoperation for AR was performed in 16 patients (1.4%; of an interval. (B) Hazard function for AR in 1,156 survivors after the 95% CI 0.9 to 2.2); all but one had a moderate or severe AR arterial switch operation. Dotted lines ϭ 95% confidence interval. 2060 Losay et al. JACC Vol. 47, No. 10, 2006 Aortic Regurgitation After Arterial Switch May 16, 2006:2057–62

Figure 3. Evolution of the aortic regurgitation at the end of the follow-up according to the aortic regurgitation grade at discharge. 0 ϭ absence, I ϭ Figure 4. (A) Actuarial survival free of reoperation for aortic regurgitation trivial, II ϭ mild, III ϭ moderate, IV ϭ severe. for the 1,156 survivors. Numbers indicate number of patients observed at the beginning of interval. (B) Hazard function for reoperation for aortic secondary valve replacement. The 13 survivors were well regurgitation in the 1,156 survivors. Dotted lines ϭ 95% confidence with good LV function and absent or trivial residual AR. interval. Abbreviations as in Figure 2. Freedom from reoperation for AR was 99.8%, 99.3%, population were the aorta pulmonary artery size discrep- 97.7%, and 96.8% at 1, 5, 10, and 15 years, respectively. The ancy, presence of AR at discharge, protective pulmonary hazard function for reoperation was low but slowly increas- artery banding, complex TGA, aortic arch obstruction, and ing from 2 years to 16 years (Fig. 4). Aortic regurgitation older age at the ASO. Multivariate analysis retained two did not significantly influence late survival (Fig. 5); at 10 factors: complex TGA and AR at discharge. If prior PAB years, actuarial survival was 98.5% in patients with AR and can cause PA distortion and facilitate late AR, presence of 96.4% in the other patients. a VSD encompasses all the others, and presence of a VSD DISCUSSION was found to be closely related to AR apparition in other recent studies (27,28). A VSD causes the two mechanisms AR prevalence and incidence. Occurrence of AR was of a pulmonary root dilation: elevated PA pressure and flow observed early in the ASO experience and reported in 30% increase through the pulmonary valve. This neo-aortic root and 55% of the patients in whom a two-stage operation was dilation was found correlated to AR in a recent study (27). performed (24–26). Later, when primary repair or rapid The observation of frequent and important pulmonary valve two-stage operation was the rule, AR prevalence decreased and ranged between 5% and 22% (12–16) after a one- to two-year follow-up. In most of the recent publications with a longer follow-up (around five years), AR is a rare com- plication, with a prevalence between 0.3% and 10% (8– 10,17) lower than that of pulmonary stenosis or coronary stenosis; one exception is a report with a prevalence of 30% of AR after 5.8 years of follow-up (7). In our population, with a 6.4 Ϯ 5 year follow-up, the prevalence of all AR was 14.9%, in accordance with other publications (8–10,17), but it was 5.9% if trivial ARs are excluded, close to the 5.1% observed in a recent study with a slightly shorter follow-up (27). Figure 5. Actuarial survival according to the presence or absence of aortic regurgitation. Lines and numbers related to subjects without aortic regur- Risk factors for AR. As found by other investigators gitation are in bold. Numbers indicate the number of patients observed at (15,24,26–28), predictive preoperative risk factors in our the beginning of an interval. Dotted lines ϭ 95% confidence interval. JACC Vol. 47, No. 10, 2006 Losay et al. 2061 May 16, 2006:2057–62 Aortic Regurgitation After Arterial Switch regurgitation after palliation of the hypoplastic left heart successive, reliable measurement of the aortic root was not syndrome is also in favor of this hypothesis (29,30). Pressure available; the relationship between aortic root size and AR increase alone is also a risk factor, as a preparatory PAB is apparition and evolution has not been assessed. correlated to AR in our population with IVS. Conclusions. As shown in this large population, an AR is Observation of an AR at discharge is the second factor not rare after ASO; ARs were present in almost 15% of the retained by multivariate analysis in this population. Presence of patients after a 75-month median follow-up and in 22% AR at discharge suggests the role of the surgical technique. after 10 years. New ARs can be observed late, after up to 16 Ventricular septal defect closure through the pulmonary valve years. Most ARs are without consequence, as 60% were in Taussig-Bing anomaly or some method of coronary artery trivial and surgery was performed in only 1.4% of the reimplantation on the neo-aortic root may induce valve lesions survivors. Occurrence of AR is related to the presence of a or aortic root distortion (10,14,15,27,31,32). It should be VSD. Surgical technique could also be a factor, as AR at mentioned that no correlation was found in our population discharge is strongly related to late AR even if some between coronary patterns and AR, although coronary regurgitations disappear shortly after surgery. Evolution of transfer is more delicate in complex coronary patterns. AR underlines the need for close long-term monitoring and AR outcome. The fate of the AR is diversely assessed. In further studies to clarify the risk factors and possibly to most of the publications, AR is not only rare but stable modify the surgical timing in some patients. without progressive aggravation (8–10,14,16). This is in accordance with the observation that no further increase of Reprint requests and correspondence: Dr. Jean Losay, Centre the Valsalva sinus occurs after some years of follow-up: 1 Chirurgical Marie-Lannelongue, 133 avenue de la Résistance, year in one study (32), 10 years in another (27). But in 92350 Le Plessis-Robinson, France. 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