Clinical Course of TGA After Arterial Switch Operation in the Current Era

Background The number of patients with an arterial switch operation (ASO) for transposition of the great arteries (TGA) is steadily growing; limited information is available regarding the clinical course in the current era. Objectives The purpose was to describe clinical outcome late after ASO in a national cohort, including survival, rates of (re-)interventions, and clinical events. Methods A total of 1,061 TGA-ASO patients (median age 10.7 years [IQR: 2.0-18.2 years]) from a nationwide prospective registry with a median follow-up of 8.0 years (IQR: 5.4-8.8 years) were included. Using an analysis with age as the primary time scale, cumulative incidence of survival, (re)interventions, and clinical events were determined. Results At the age of 35 years, late survival was 93% (95% CI: 88%-98%). The cumulative re-intervention rate at the right ventricular outflow tract and pulmonary branches was 36% (95% CI: 31%-41%). Other cumulative re-intervention rates at 35 years were on the left ventricular outflow tract (neo-aortic root and valve) 16% (95% CI: 10%-22%), aortic arch 9% (95% CI: 5%-13%), and coronary arteries 3% (95% CI: 1%-6%). Furthermore, 11% (95% CI: 6%-16%) of the patients required electrophysiological interventions. Clinical events, including heart failure, endocarditis, and myocardial infarction occurred in 8% (95% CI: 5%-11%). Independent risk factors for any (re-)intervention were TGA morphological subtype (Taussig-Bing double outlet right ventricle [HR: 4.9, 95% CI: 2.9-8.1]) and previous pulmonary artery banding (HR: 1.6, 95% CI: 1.0-2.2). Conclusions TGA-ASO patients have an excellent survival. However, their clinical course is characterized by an ongoing need for (re-)interventions, especially on the right ventricular outflow tract and the left ventricular outflow tract indicating a strict lifelong surveillance, also in adulthood.

D extro-transposition of the great ar- teries (TGA) is a complex cyanotic congenital malformation and represents approximately 5% to 7% of all congenital heart defects. 1 Nowadays, surgical repair is performed several days after birth by the arterial switch operation (ASO).
4][5] Previous studies on survival, (re)interventions, and clinical events after ASO are often limited because of their retrospective nature, small cohort size and by a possible bias due to an excess of events in patients operated in the early years with lack of experience of the surgical team.Surgical modifications have been applied since the first ASO including Lecompte maneuver, coronary reimplantation technique, and RVOT reconstruction.Whether clinical outcomes in the early decades after ASO are still applicable to nowadays care in the 21st century is unknown.Therefore, we used prospectively collected data from a nationwide registry from the current era to investigate the clinical course of patients with TGA after ASO, especially for the survival, the need for (re-)interventions and clinical events.

METHODS
STUDY POPULATION.All patients diagnosed with TGA including the various subtypes, TGA with intact ventricular septum (TGA-IVS), TGA with ventricular septal defect (TGA-VSD), and Taussig-Bing double outlet right ventricle (TB-DORV) with subpulmonary VSD were included.Prospectively collected data were obtained from: 1) a national registry for pediatric patients with congenital heart disease (KinCor registry) 6 ; and 2) a national registry for adult patients with Congenital Corvitia (CONCOR registry). 7Informed consent was obtained from all Kincor or Concor patients.The study was approved by the Medical Ethical Committee of the Amsterdam and Leiden University Medical Center and complies with the Declaration of Helsinki.
DATA COLLECTION.A query was performed to identify all TGA patients after ASO from the KinCor and Concor registry.The number of included patients in the registries corresponds to 75% to 80% of eligible patients and with 95 % of all the patients who were asked for participation. 6Patients were excluded based on the following criteria; prior surgical repair before ASO (eg, atrial switch) and lost to follow-up (no available follow-up data after inclusion).Baseline characteristics at the time of inclusion and all prospectively follow-up data (at least 30 days after ASO) were collected (period February 2001-July (RStudio).Values of P < 0.05 were considered to be statistically significant.
One patient underwent a catheter-related neo-aortic valve procedure.Cumulative incidence of LVOT reintervention during follow-up was 6% (95% CI: 3%-9%) at 20 years, 10% (95% CI: 6%-14%) at 30 years, and 16% (95% CI: 10%-22%) at 35 years (Figure 3).On multivariable analysis, complex morphological subtype (TB-DORV) was an independent risk factor for LVOT re-intervention (HR: 6.1, 95% CI: 2.5-14.9,P < 0.001).(n ¼ 1).In 1 case, endocarditis led to the demise of the patient.Furthermore, 1 asymptomatic patient (age 31 years) was diagnosed with an old myocardial infarction and 1 symptomatic patient (age 27 years) presented with an acute coronary syndrome.Cumulative incidence of a clinical event at 35 years was 4% (95% CI: 0%-7%) in TGA-IVS (Figure 1A), 12% (95% CI: 5%-19%) in TGA-VSD (Figure 1B), and 23% (95% CI: 2%-43%) in TB-DORV (Figure 1C).     the age of 35 years in the general Dutch population, survival after ASO is still lower.In contrast to all previous retrospective studies with inclusion of events from the early decades after ASO, our prospective analysis on outcome (with age as the primary time scale) in exclusively the 21st century gives in our view a more up to date estimate of the clinical course of TGA-ASO patients in the current era.In this study, we demonstrated that (re-)intervention rates appeared to be high and linear with age, the cumulative incidence of (re-)intervention at the age of 35 years was 52%.However, this rate is still lower compared to a morbidity rate of 81% at 39 years after atrial switch. 9THODOLOGICAL APPROACH.In the current study, prospectively collected data from 2 nationwide registries with inclusion of pediatric and adult TGA-ASO patients were analyzed.Age was used as the primary time scale and allowed us to describe the clinical course of TGA-ASO patients regarding clinical events and (re-)interventions.With this approach, we did account for the confounding effect of age and information bias was avoided.Re-interventions or clinical events before inclusion were not part of the prospective analysis.[12] Therefore, we are confident that our results fairly

Engele et al
in 1975 and involves translocation of the great arteries and reimplantation of the coronary arteries to achieve anatomical correction of the circulation.Despite the anatomical repair, complications during follow-up after ASO are common including obstructions in the right ventricular outflow tract (RVOT)

A
B B R E V I A T I O N S A N D A C R O N Y M S ASO = arterial switch operation DORV = double outlet right ventricle ICD = implantable cardioverter defibrillator IVS = intact ventricular septum LVOT = left ventricular outflow tract PAB = pulmonary artery banding RVOT = right ventricular outflow tract TB = Taussig-Bing TGA = transposition of the great arteries VSD = ventricular septum defect Cardiology, University Medical Center Groningen, Groningen, the Netherlands; h Department of Pediatric Cardiology, Centre for Congenital Heart Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; i Department of Cardiothoracic Surgery, University Medical Center Groningen, Groningen, the Netherlands; 2022).Follow-up ended at the most recent outpatient clinic contact.Patients were censored at the time of follow-up.Duplicated patients between the pediatric and adult database were identified based on diagnosis, ASO date, center and sex and subsequently removed.Quality checks were performed and consisted of identifying incomplete or inconsistent information and were resolved on a per-patient basis.ENDPOINTS.Demographics and follow-up data, including reoperations, catheter-based interventions, and clinical events were analyzed.We aimed to describe the long-term outcome without early postoperative complications, therefore only clinical events, mortality, and re-interventions (surgery and catheter-based interventions) at least 30 days after ASO were included.Patients who died within 30 days after ASO were excluded from the analysis.Based on the localization, re-interventions were classified in the following categories: 1) RVOT, including reinterventions at the level of the pulmonary branches, main pulmonary artery, pulmonary valve or subpulmonary valve; 2) left ventricular outflow tract (LVOT), including re-interventions at the neoaortic valve and neo-aortic root; 3) coronary arteries including any coronary revascularization procedure; 4) aortic arch; and 5) miscellaneous, including reinterventions at the mitral and tricuspid valve, atrial or ventricular septum.Electrophysiological interventions were included separately and consisted of catheter-ablation for supraventricular or ventricular arrhythmia and implantation of an implantable cardioverter-defibrillator (ICD) or pacemaker.The following clinical events were included: endocarditis, myocardial infarction, heart failure, cardiac arrest, and late mortality.Myocardial infarction was defined as hospital admission for the presence of ST-segment elevation due to an acute coronary syndrome or patients with coronary occlusion with fibrotic scar or perfusion defect in the corresponding area.Heart failure episode was defined as the need for hospitalization for heart failure and assessed primary by the treating physician or by research nurse.Patients without any available followup data were considered as lost to follow-up.Only late mortality (>30 days after ASO) was included and classified when available.STATISTICAL ANALYSIS.Data were summarized as number (%) for categorical variables and mean AE SD for continuous variables with normal distribution.Continuous data with skewed distribution were described by median (IQR).Baseline comparisons between TGA-IVS, TGA-VSD, and TB-DORV were performed by 1-way analysis of variance, Kruskal-Wallis tests, or chi-squared test, where appropriate.Factors associated with (re-)intervention were explored in univariable Cox regression analysis and only variables significant in univariable analysis were analyzed in multivariable Cox regression.For time-to-event analyses, patient-time was accrued until the outcome of interest (RVOT re-intervention, LVOT re-intervention, coronary intervention, electrophysiological intervention, and clinical event) with right censoring at the moment of the last follow-up.Cumulative incidence rates of (re-)interventions and clinical events with age as a time scale were adjusted for the competing risk of death and estimated for first occurrence of each outcome using a delayed entry method (R package survival) for left truncated data.Spline interpolation was used to report on the cumulative incidence estimates at the age of 40 years.Statistical analyses were performed using SPSS V.20 (IBM) and R v.4.0.3.
DORV.Two patients (age 22 and 35 years) died due to progressive heart failure and in 1 patient (age 25 years) acute heart failure was the cause of death.Furthermore, 2 patients died after stent implantation in the pulmonary artery; in 1 patient (age 19 years) death was attributable to pulmonary artery embolism postprocedure and in the second patient (age 17 years) autopsy revealed an iatrogenic aorta pulmonary fistula.Infectious cause was present in 2 cases; 1 patient (age 28 years) died due to endocarditis of a Bentall prosthesis with severe neurological complications and the second patient (age 22 years) was diagnosed with lymphocytic myocarditis and died due to sudden cardiac death.One patient (age 2 months) passed away after cardiac

FIGURE 1 4
FIGURE 1 Cumulative Incidence of (Re-)Intervention, Clinical Event, and Death in TGA-ASO

FIGURE 2
FIGURE 2 Sankey Diagram of Patients With One or Multiple (Re-)Interventions After ASO

JClinical
A C C : A D V A N C E S , V O L . 3 , N O . 2 Course of TGA After ASO DISCUSSION In this large nationwide prospective cohort study, consisting of 1,061 TGA patients after ASO, we estimated cumulative incidence rates for (re-)intervention and clinical event after ASO.This study reported a late survival of 93% at 35 years, showing that in the current era patients after ASO have an excellent longterm survival compared to a 64% survival at 40 years as assessed in a recently published meta-analysis of dextro-TGA patients corrected by the atrial switch. 8owever, compared to the survival rate of 98.7% at

FIGURE 4
FIGURE 4 Cumulative Incidence of First and Subsequently RVOT Re-Intervention in TGA-ASO

FIGURE 3
FIGURE 3 Cumulative Incidence of (Re-)Intervention in TGA-ASO

Clinical
INTERVENTIONS.In both pediatric and adult ASO survivors, RVOT re-intervention was the most frequent re-intervention.The cumulative incidence was 36% at the age of 35 years and showed a linear relationship between RVOT re-intervention rate and age indicating that the need for RVOT reintervention after ASO is not limited to a certain time frame but continues during adulthood.Santens et al13 reported a re-intervention rate of 21% at 20 years in their retrospective long-term follow-up analysis, which is in contrast to the re-intervention rate of 28% at 20 years in our study.However, this higher rate may be explained by our definition of RVOT interventions, which was not restricted to reinterventions at the pulmonary arteries but also included pulmonary valve replacements.In our study, the median age of the first RVOT reintervention was 13.8 years and is different than in other studies in which the age of first RVOT reintervention varied between 9 months and 3.8 years,[14][15][16] probably caused by the longer observation period and the continuation of the need for intervention at older age.Patients with complex TGA subtype (DORV) were at increased risk for RVOT re-intervention, indicating the impact of this complex morphology on the clinical course.No association was found between the era in which the ASO was performed and the incidence of RVOT re-intervention probably as a result of the ongoing interventions also in adulthood.LVOT RE-INTERVENTIONS.In our study, the cumulative incidence of patients who required a reintervention at the LVOT was 7% at the age of 25 years.This finding agrees with the results of a recent retrospective study by Fricke et al 10 who reported a freedom from neo-aortic re-intervention of 92% at 25 years.As most of these patients underwent neo-aortic re-interventions during adulthood (median age 21.3 years), it is expected that the number of re-interventions will increase as the follow-up lengthens.Literature on the progression of aortic root dilatation during lifetime is contradictory.Schwartz et al 17 observed no further increase of neoaortic root diameter 10 years after ASO.However, more recent studies in both children and adults found no stabilization of neo-aortic growth and reported an average growth rate of the neo-aortic root of 0.63 mm/year. 18In multivariable analysis, PAB was independently associated with LVOT re-intervention, which could be explained by stenosis and distortion due to banding of the pulmonary artery which facilitate neo-aortic regurgitation.Furthermore, analysis between TGA subtypes showed that TB-DORV was associated with LVOT re-intervention but we did not find, in contrary to other studies, an association in TGA-VSD patients.In our study, the cumulative incidence at 35 years was 16%, which demonstrates the ongoing risk for aortic root dilatation and aortic valve regurgitation during lifetime.Close surveillance of the neo-aorta in patients with or without risk factors seems to be indicated.CORONARY ARTERIES.With a cumulative incidence of 3% at the age of 35 years, the number of late reintervention at the coronary arteries appeared to be low.This low rate is in line with current literature on late coronary complications after ASO. 19Of the 7 patients who underwent coronary re-intervention, only 2 patients experienced complaints of angina pectoris.In 5 asymptomatic patients, detection of coronary abnormality was based on routine exercise stress testing or cardiac imaging.The absence of angina pectoris in patients with coronary abnormalities may be due to denervation caused by transection of the great arteries and reimplantation of the coronary arteries. 20In contrast to previous studiesCourse of TGA After ASO re-interventions, which may be explained by the low number of late coronary re-interventions in our study.None of the coronary re-interventions or coronary events were associated with late mortality.Although the optimal follow-up strategy of the coronary arteries is a contentious issue, our findings of a low cumulative incidence of coronary events and re-interventions does not support an aggressive routinely strategy regarding the clinical evaluation of the coronary arteries.

CLINICAL IMPLICATIONS. 4 Clinical
The cumulative incidence of a first re-intervention after ASO was 60% at 40 years, demonstrating the ongoing need for reinterventions after ASO.Long-term outcome after the age of 40 years is still unknown, however based on current re-intervention rates it may be expected that the number of patients with a first (re-)intervention will raise as the ASO population ages.Based on an estimated re-intervention rate of 14.9% per decade with a linear relationship with age, one could CENTRAL ILLUSTRATION Clinical Course of TGA After ASO: Mortality and Re-Intervention Rates at 35 Years Engele LJ, et al.JACC Adv.2024;3(2):100772.The figure demonstrates the clinical course of TGA after ASO at the age of 35 year.The mortality and re-intervention rates represents the calculated cumulative incidence at the age of 35 years for RVOT re-intervention, LVOT re-intervention, coronary artery re-intervention and death.The dotted line (and question mark) reflects the period after 35 years, in which the outcome is still unknown.ASO ¼ arterial switch operation; LVOT ¼ left ventricular outflow tract; RVOT ¼ right ventricular outflow tract.Engele et al J A C C : A D V A N C E S , V O L . 3 , N O . 2 , 2 0 2 Course of TGA After ASO F E B R U A R Y 2 0 2 4 : 1 0 0 7 7 2

20.
Kuehn A, Vogt M, Schwaiger M, Ewert P, Hauser M. Ventricular sympathetic innervation in patients with transposition of the great arteries after arterial switch operation and Rastelli procedure: impact of arterial dissection and coronary reimplantation.Circ J. 2014;78(7):1717-1722. KEY WORDS arterial switch operation, long-term outcome, re-intervention, transposition of the great arteries APPENDIX For supplemental tables and figures, please see the online version of this paper.

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A C C : A D V A N C E S , V O L . 3 , N O . 2 , 2 0 2 4Clinical Course of TGA After ASOF E B R U A R Y 2 0 2 4 : 1 0 0 7 7 2

TABLE 1
Baseline CharacteristicsValues are n (%) or median (IQR).Clinical characteristics of the study population at baseline in accordance with TGA subtype.a P value represents the simple comparisons between groups (Fisher exact test, Kruskal-Wallis or 1-way ANOVA).b Systemic to pulmonary artery shunt.

TABLE 3
Univariable and Multivariable Cox Proportional Hazard Analysis for (Re-)Intervention After ASO a P value represents the P value for univariable Cox proportional hazards regression.b P value for multivariable Cox proportional hazards regression.ASO ¼ arterial switch operation; IVS ¼ intact ventricular septum; PA ¼ pulmonary artery; TB-DORV ¼ Taussig Bing double outlet right ventricle; TGA ¼ transposition of the great arteries; VSD ¼ ventricular septum defect.
speculate a re-intervention rate up to 90% at the age of 60 years.Therefore, regular follow-up with focus on both RVOT and LVOT seems necessary.The number of coronary re-interventions and coronary events appeared to be very low (Central Illustration).The ongoing need for (re-)intervention highlights that a strict lifelong surveillance, also in adulthood remains necessary.FUNDING SUPPORT AND AUTHOR DISCLOSURESSupport was received from the Netherlands Cardiovascular Research lnitiative: An initiative with support of the Dutch Heart Foundation and Hartekind, CVON2019-002 OUTREACH.The authors have reported that they have no relationships relevant to the contents of this paper to disclose.transposition of the great arteries.A 35-year follow-up study.Int J Cardiol.2020;316:94-100.14. Williams WG, Quaegebeur JM, Kirklin JW, Blackstone EH.Outflow obstruction after the arterial switch operation: a multiinstitutional study.Congenital Heart Surgeons Society.15. van der Palen RLF, Blom NA, Kuipers IM, et al.Long-term outcome after the arterial switch operation: 43 years of experience.Eur J Cardio Thorac Surg.2021;59(5):968-977.16.Cleuziou J, Vitanova K, Pabst von Ohain J, et al.Incidence and risk factors for right ventricular outflow tract obstruction after the arterial switch operation.Thorac Cardiovasc Surg.2019;67(1):37-43.17.Schwartz ML, Gauvreau K, del Nido P, Mayer JE, Colan SD.Long-term predictors of aortic root dilation and aortic regurgitation after arterial switch operation.Circulation.2004;110(11 Suppl 1):II128-II132.18. van der Palen RLF, van der Bom T, Dekker A, et al.Progression of aortic root dilatation and aortic valve regurgitation after the arterial switch operation.Heart.2019;105(22):1732-1740. 19.Engele LJ, Mulder BJM, Schoones JW, et al.
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