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JACC Adv. 2024 Feb; 3(2): 100772.
Published online 2023 Dec 27. doi:10.1016/j.jacadv.2023.100772
PMCID: PMC11198364
PMID: 38939383
Leo J. Engele, MD,a,b Roel L.F. van der Palen, MD, PhD,c Renée S. Joosen, MD,d Gertjan T. Sieswerda, MD, PhD,e Paul H. Schoof, MD, PhD,f Joost P. van Melle, MD, PhD,g Rolf M.F. Berger, MD, PhD,h Ryan E. Accord, MD,i Lukas A.J. Rammeloo, MD,j Thelma C. Konings, MD,k Wim A. Helbing, MD, PhD,l Jolien W. Roos-Hesselink, MD, PhD,m Pieter C. van de Woestijne, MD,n Stefan Frerich, MD, PhD,o Arie P.J. van Dijk, MD, PhD,p,q Irene M. Kuipers, MD, PhD,r Mark G.H. Hazekamp, MD, PhD,s Barbara J.M. Mulder, MD, PhD,a,b Johannes M.P.J. Breur, MD, PhD,d Nico Blom, MD, PhD,c,r Monique R.M. Jongbloed, MD, PhD,t,u,∗ and Berto J. Bouma, MD, PhDa,b,∗∗
Author information Article notes Copyright and License information PMC Disclaimer
See editorial "Arterial Switch Operation for Transposition of the Great Arteries" in volume 3, 100771.
Associated Data
- Supplementary Materials
Abstract
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 10.7years [IQR: 2.0-18.2 years]) from a nationwide prospective registry with a median follow-up of 8.0years (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 35years, 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 35years 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.
Key words: arterial switch operation, long-term outcome, re-intervention, transposition of the great arteries
Central Illustration
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Dextro-transposition of the great arteries (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). The ASO was introduced by Jatene etal2 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) and pulmonary branch stenosis due to the LeCompte maneuver, neo-aortic valve regurgitation due to neo-aortic root dilatation and coronary artery obstruction, although reported with various incidences.3, 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).7 Informed 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.6 Patients 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 30days after ASO) were collected (period February 2001-July 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 30days after ASO were included. Patients who died within 30days after ASO were excluded from the analysis. Based on the localization, re-interventions were classified in the following categories: 1) RVOT, including re-interventions 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 neo-aortic valve and neo-aortic root; 3) coronary arteries including any coronary revascularization procedure; 4) aortic arch; and 5) miscellaneous, including re-interventions 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 follow-up data were considered as lost to follow-up. Only late mortality (>30days after ASO) was included and classified when available.
Statistical analysis
Data were summarized as number (%) for categorical variables and mean±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 40years. Statistical analyses were performed using SPSS V.20 (IBM) and Rv.4.0.3. (RStudio). Values of P < 0.05 were considered to be statistically significant.
Results
Patients
A total of 1,117 TGA-ASO patients were identified from the Kincor and Concor registry (Supplemental Table1). Forty-three (3.7%) patients were lost to follow-up because they lived abroad (n=21) or for reasons that are unknown (n=22). Nine (0.8%) patients who died within 30days after ASO and 4 (0.4%) patients who underwent atrial switch procedure prior to ASO were excluded. We included 1,061 patients, which were actively followed in 8 tertiary hospitals in the Netherlands. ASO was performed in 4 university medical centers. The diagnoses of patients included 696 (66%) TGA-IVS, 307 (29%) TGA-VSD, and 58 (5%) with TB-DORV. The median age at inclusion was 10.7 (IQR: 2.0-18.2, range 0-43) years. Pulmonary artery banding (PAB) was performed in 6% of the patients to prepare for the switch operation and 32% of the patients did have a surgical atrial septectomy or balloon atrial septostomy (Rashkind) procedure prior to ASO. Aortic arch abnormalities were present in 91 (9%) patients. The median age at ASO was 9days (IQR: 6-19days). Table1 summarizes all baseline characteristics.
Table1
Baseline Characteristics
| All Patients (n=1,061) | TGA-IVS (n=696) | TGA-VSD (n=307) | TB-DORV (n=58) | P Valuea | |
|---|---|---|---|---|---|
| Male | 734 (69.2%) | 495 (71.1%) | 197 (64.2%) | 42 (72.4%) | 0.084 |
| Age, y | 10.7 (2.0-18.2) | 10.9 (2.6-18.2) | 11.0 (2.0-18.1) | 5.6 (0.3-14.9) | 0.026 |
| Coexisting findings | |||||
| Aortic arch abnormality | 91 (8.6%) | 18 (2.6%) | 43 (14.0%) | 30 (51.7%) | <0.001 |
| Preoperative procedures | |||||
| Rashkind/atrial septectomy | 336 (31.7%) | 239 (34.3%) | 85 (27.7%) | 12 (20.7%) | 0.021 |
| PAB | 67 (6.3%) | 25 (3.6%) | 34 (11.1%) | 8 (13.8%) | <0.001 |
| Modified Blalock-Taussig shuntb | 29 (2.7%) | 14 (2.0%) | 14 (4.6%) | 1 (1.7%) | 0.066 |
| Arterial switch operation | |||||
| Age, d | 9 (6-19) | 8 (5-13) | 11 (7-37) | 39 (12-82) | <0.001 |
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Values are n (%) or median (IQR).
Clinical characteristics of the study population at baseline in accordance with TGA subtype.
IVS=intact ventricular septum; PAB=pulmonary artery banding; TB-DORV=Taussig Bing double outlet right ventricle; TGA=transposition of the great arteries; VSD=ventricular septum defect.
aP value represents the simple comparisons between groups (Fisher exact test, Kruskal-Wallis or 1-way ANOVA).
bSystemic to pulmonary artery shunt.
Survival
Patients were followed for a median period of 8.0 (IQR: 5.4-8.8, range 0-21) years. Forty-nine percent of the patients were older than 18years at the end of follow-up. Twelve (1.1%) patients died during late follow-up (more than 30days after surgery) at a median age of 23.1years (IQR: 20.4-29.1 years). TGA subtypes in these patients were 6(0.6%) TGA-IVS, 3 (0.3%) TGA-VSD, and 3 (0.3%) TB-DORV. Two patients (age 22 and 35years) died due to progressive heart failure and in 1 patient (age 25years) acute heart failure was the cause of death. Furthermore, 2 patients died after stent implantation in the pulmonary artery; in 1 patient (age 19years) death was attributable to pulmonary artery embolism postprocedure and in the second patient (age 17years) autopsy revealed an iatrogenic aorta pulmonary fistula. Infectious cause was present in 2 cases; 1 patient (age 28years) died due to endocarditis of a Bentall prosthesis with severe neurological complications and the second patient (age 22years) was diagnosed with lymphocytic myocarditis and died due to sudden cardiac death. One patient (age 2months) passed away after cardiac arrest (ventricular fibrillation), but autopsy was not performed. In one 14-year-old patient, death was attributable to septic shock. Data on cause of death could not be retrieved in 3 patients. Late survival at35years was 95% (95%CI: 91%-100%) in TGA-IVS (Figure1A), 91% (95%CI: 81%-100%) inTGA-VSD (Figure1B), and 69% (95%CI: 39%-96%) inTB-DORV (Figure1C). For the total cohort, survival at 35years was 93% (95%CI: 88%-98%) (Figure1D).
Figure1
Cumulative Incidence of (Re-)Intervention, Clinical Event, and Death in TGA-ASO
Cumulative incidence of first (re-)intervention during follow-up; all (re-)intervention (red), clinical event (blue) and death (green) in TGA-IVS (A), TGA-VSD (B), TB-DORV (C), all TGA subtypes (D). Cumulative incidence rates with age as a time scale were estimated for first occurrence of each outcome using a delayed entry method (R package survival) for left truncated data. (D) shows the cumulative incidence, calculated with spline interpolation, until the age of 40years. ASO=arterial switch operation; IVS=intact ventricular septum; TB-DORV=Taussig Bing double outlet right ventricle; TGA=transposition of the great arteries; VSD=ventricular septum defect.
(RE-)interventions
In total, 240 (re-)interventions in 144 (13.6%) patients were performed during prospective follow-up, all (re-)interventions are listed in Table2. Among TGA subgroups, the distribution of (re-)interventions was 76 (11%) in TGA-IVS, 42 (14%) in TGA-VSD, and 26 (45%) in TB-DORV. The median age at (re-)intervention was 17.8 (IQR: 9.3-22.5) years in TGA-IVS, 17.5 (IQR: 7.9-27.6) years in TGA-VSD, and 2.9 (IQR: 0.8-14.4) years in TB-DORV. Cumulative incidence of any (re-)intervention (n=144) within the prospective follow-up interval 2001 to 2022 at the age of 35years was 44% (95%CI: 39%-48%) in TGA-IVS (Figure1A), 54% (95%CI: 48%-59%) in TGA-VSD (Figure1B), and 88% (95%CI: 80%-96%) in TB-DORV (Figure1C). The following univariable risk factors (Table3) were significantly associated with any (re-)intervention post-ASO: morphological subtype (TB-DORV) and PAB. Independent risk factors included TB-DORV (HR: 4.9, 95%CI: 2.9-8.1, P<0.001) and PAB (HR: 1.6, 95%CI: 1.0-2.2, P=0.040) (Table3 and Supplemental Figure1). Figure 2 shows the number of patients with single or multiple (re-)interventions post-ASO.
Table2
Overview of the Number of (Re-)Interventions in TGA-ASO During Prospective Follow-Up
| Total Re-Interventions | Re-Interventions in TGA-IVS (n=696) | Re-Interventions in TGA-VSD (n=307) | Re-Interventions in TB-DORV (n=58) | |
|---|---|---|---|---|
| Right ventricular outflow tract | 127 | 71 | 39 | 17 |
| Catheter-related intervention | ||||
| Dilatation or stent implantation | 77 | 48 | 20 | 9 |
| Surgical re-intervention | ||||
| Repair RVOT | 38 | 17 | 13 | 8 |
| Pulmonary valve replacement | 12 | 6 | 6 | 0 |
| Left ventricular outflow tract | 37 | 16 | 12 | 9 |
| Catheter-related intervention | ||||
| Neo-aortic root/valve | 1 | 0 | 1 | 0 |
| Surgical re-intervention | ||||
| Bentall procedure | 19 | 9 | 7 | 3 |
| Neo-aortic valve replacement | 8 | 4 | 2 | 2 |
| Neo-aortic valve plasty | 5 | 1 | 1 | 3 |
| Othera | 4 | 2 | 1 | 1 |
| Aortic arch | 21 | 1 | 9 | 11 |
| Catheter-related intervention | ||||
| Dilatation or stent implantation | 11 | 0 | 2 | 9 |
| Surgical re-intervention | ||||
| Aortic arch repair | 10 | 1 | 7 | 2 |
| Coronary arteries | 7 | 4 | 1 | 2 |
| Catheter-related intervention | ||||
| Dilatation or stent implantation | 1 | 1 | 0 | 0 |
| Surgical re-intervention | ||||
| Ostial plasty | 2 | 0 | 1 | 1 |
| CABG | 4 | 3 | 0 | 1 |
| Electrophysiological interventions | 32 | 14 | 13 | 5 |
| Ablation procedure | 19 | 9 | 8 | 2 |
| ICD placement | 8 | 4 | 3 | 1 |
| Pacemaker placement | 5 | 1 | 2 | 2 |
| Miscellaneousb | 16 | 3 | 9 | 4 |
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Values are n. Bold values represents the total number of re-interventions in each category.
ASO=arterial switch operation; CABG=coronary artery bypass grafting; DORV=double outlet right ventricle; ICD=implantable cardioverter defibrillator; IVS=intact ventricular septum; RVOT=right ventricular outflow tract; TB=Taussig Bing; TGA=transposition of the great arteries; VSD=ventricular septum defect.
aPersonalized external aortic root support (Pears) (n=3) and surgical relief of LVOT obstruction (n=1).
bMitral valve plasty (n=7), ventricular septum defect closure (n=6), tricuspid valve plasty (n=2), and atrial septum defect closure (n=1).
Table3
Univariable and Multivariable Cox Proportional Hazard Analysis for (Re-)Intervention After ASO
| Risk Factors | Univariable | Multivariable | ||||
|---|---|---|---|---|---|---|
| HR | 95%CI | P Valuea | HR | 95%CI | P Valueb | |
| Data source | ||||||
| Concor registry | 1.00 | |||||
| KinCor registry | 1.20 | 0.88-1.56 | 0.564 | |||
| Morphological subtype | ||||||
| TGA-IVS | 1.00 | 1.00 | ||||
| TGA-VSD | 0.92 | 0.62-1.36 | 0.673 | 1.17 | 0.78-1.80 | 0.441 |
| TB-DORV | 5.65 | 3.58-8.91 | 0.001 | 4.86 | 2.92-8.10 | 0.001 |
| Sex | ||||||
| Male | 1.00 | |||||
| Female | 1.06 | 0.73-1.54 | 0.767 | |||
| Prior PA banding | ||||||
| No | 1.00 | 1.00 | ||||
| Yes | 1.66 | 1.24-2.19 | 0.006 | 1.60 | 1.02-2.21 | 0.040 |
| Era of ASO (<2,000) | ||||||
| No | 1.00 | |||||
| Yes | 0.18 | 0.11-0.29 | 0.071 | |||
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ASO=arterial switch operation; IVS=intact ventricular septum; PA=pulmonary artery; TB-DORV=Taussig Bing double outlet right ventricle; TGA=transposition of the great arteries; VSD=ventricular septum defect.
aP value represents the P value for univariable Cox proportional hazards regression.
bP value for multivariable Cox proportional hazards regression.
Figure2
Sankey Diagram of Patients With One or Multiple (Re-)Interventions After ASO
Sankey diagram: demonstrating the number of patients with single or multiple (re-)interventions after the arterial switch operation, categorized by the type of (re-)intervention. Electrophysiological (re-)interventions includes ablation, ICD and pacemaker placement. ASO=arterial switch operation; LVOT=left ventricular outflow tract; RVOT=right ventricular outflow tract.
Right ventricular outflow tract
A total number of 95 (9.0%) patients underwent 127 re-interventions at the site of the RVOT, consisting of 50 reoperations and 77 catheter-based procedures (Table2). During prospective follow-up, RVOT re-interventions were performed in 55 (8%) TGA-IVS patients at the median age of 13.6 (IQR: 7.7-20.3) years, in 28 (9%) patients with TGA-VSD at the median age of 13.7 (IQR: 4.8-20.0) years, and in 12 (21%) patients with TB-DORV at the median age of 1.1 (IQR: 0.8-3.5) years. The cumulative incidence of RVOT re-intervention for all TGA subtypes at 10, 20, 30, and 35years was, respectively, 17% (95%CI: 13%-21%), 28% (95%CI: 23%-31%), 32% (95%CI: 27%-36%), and 36% (95%CI: 31%-41%) (Figure3) with a linear relationship between age and the cumulative RVOT re-intervention rate. Cumulative incidence in patients with≥1 (n=95),≥2 (n=20), or 3 (n=4) consecutive RVOT re-interventions during follow-up was, respectively, 36% (95%CI: 31%-41%), 7% (95%CI: 3%-10%), and 2% (95%CI: 0%-2%) (Figure4) at age 35years. In patients with a complex morphological subtype (TB-DORV), the RVOT re-intervention rate was significantly higher (HR: 3.2, 95%CI: 1.7-6.4, P<0.001).
Figure3
Cumulative Incidence of (Re-)Intervention in TGA-ASO
Cumulative incidence of first re-intervention during follow-up; all (re-)intervention (red), RVOT re-intervention (blue), LVOT re-intervention (green), and coronary artery re-intervention (purple) in TGA patients after ASO. Cumulative incidence rates with age as a time scale were estimated for first occurrence of each outcome using a delayed entry method (R package survival) for left truncated data. ASO=arterial switch operation; LVOT=left ventricular outflow tract; RVOT=right ventricular outflow tract; TGA=transposition of the great arteries.
Figure4
Cumulative Incidence of First and Subsequently RVOT Re-Intervention in TGA-ASO
Cumulative incidence of first (red) and subsequently (blue and green) RVOT re-intervention within the follow-up period in TGA patients after ASO. Cumulative incidence rates with age as a time scale were estimated for each outcome using a delayed entry method (R package survival) for left truncated data. ASO=arterial switch operation; RVOT=right ventricular outflow tract; TGA=transposition of the great arteries.
Left ventricular outflow tract
The number of re-interventions at the LVOT (neo-aortic root and neo-aortic valve) was 37 (3.5%), which were performed in 15 (2%) patients with TGA-IVS (median age 23.0 [IQR: 18.3-26.9] years), 14 (5%) patients with TGA-VSD (median age 26.3 [IQR: 16.7-28.9] years), and 8 (14%) patients with TB-DORV (median age 16.3 [IQR: 15.1-20.6] years. Most common neo-aortic re-interventions included Bentall procedures (n=19) and neo-aortic valve replacements (n=8) (Table2). One patient underwent a catheter-related neo-aortic valve procedure. Cumulative incidence of LVOT re-intervention during follow-up was 6% (95%CI: 3%-9%) at 20years, 10% (95%CI: 6%-14%) at 30years, and 16% (95%CI: 10%-22%) at 35years (Figure3). 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).
Aortic arch
Re-intervention at the aortic arch was performed in 1 (0.1%) patient with TGA-IVS (median age 7.8), 9 (3%) patients with TGA-VSD (median age 6.9 [IQR: 3.1-13.4] years), and 11 (19%) patients with TB-DORV (median age 4.5 [IQR: 1.2-9.5] years), consisting of 11 catheter-related procedures (dilatation or stent placement) and 10 surgical procedures. The cumulative incidence was 9% (95%CI: 5%-13%) at 35years. Independent risk factors for aortic arch re-intervention were aortic arch abnormality (HR: 3.0, 95%CI: 1.3-6.3, P<0.001) and morphological subtype (TB-DORV) (HR: 4.2, 95%CI: 2.1-6.6, P<0.001).
Coronary arteries
During the follow-up period, 7 (0.7%) patients required a re-intervention at the coronary arteries at a median age of 17.0years (IQR: 9.5-25.9 years). Four patients underwent coronary artery bypass grafting for coronary artery occlusion. All 4 patients showed signs of ischemia during exercise stress test or during cardiac stress imaging, however only 1 patient was symptomatic. Catheter-related coronary re-intervention for ostium stenosis of the left coronary artery was performed in 1 asymptomatic patient. Two patients underwent coronary plasty; 1 asymptomatic patient with functional occlusion of the left main and 1 symptomatic patient with stenosis of the left main. The cumulative incidence at 35years was 3% (95%CI: 1%-6%). TGA subtype (TGA-VSD or TB-DORV) and surgical era (before 2000) were not significantly associated with coronary re-intervention in our cohort.
Electrophysiological interventions
Nineteen (1.8%) patients underwent catheter ablation therapy for supraventricular (n=11) or ventricular (n=8) arrhythmia at a median age of 24.1years (IQR: 20.5-28.4 years). Implantation of a pacemaker device for atrioventricular block was performed in 5 patients (0.5%) and 8 patients (0.8%) underwent ICD implantation because of ventricular arrhythmia. The cumulative incidence of any electrophysiological intervention was 4% (95%CI: 1%-6%) at 20years and 11% (95%CI: 6%-16%) at 35years.
Clinical events
A total of 17 (1.6%) patients had at least 1 clinical event during follow-up, consisting of endocarditis (n=8), heart failure (n=8), myocardial infarction (n=2), and cardiac arrest (n=1). In 1 case, endocarditis led to the demise ofthe patient. Furthermore, 1 asymptomatic patient(age 31years) was diagnosed with an old myocardial infarction and 1 symptomatic patient (age 27years) presented with an acute coronary syndrome. Cumulative incidence of a clinical event at 35years was 4% (95%CI: 0%-7%) in TGA-IVS (Figure1A), 12% (95%CI: 5%-19%) in TGA-VSD (Figure1B), and 23% (95%CI: 2%-43%) in TB-DORV (Figure1C).
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 35years, showing that in the current era patients after ASO have an excellent long-term survival compared to a 64% survival at 40years as assessed in a recently published meta-analysis of dextro-TGA patients corrected by the atrial switch.8 However, compared to the survival rate of 98.7% at the age of 35years 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 35years was 52%. However, this rate is still lower compared to a morbidity rate of 81% at 39years after atrial switch.9
Methodological 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. Our results were rather comparable with previous reported outcome after ASO.10, 11, 12 Therefore, we are confident that our results fairly represent a contemporary cohort of TGA-ASO patients.
RVOT re-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 35years and showed a linear relationship between RVOT re-intervention rate and age indicating that the need for RVOT re-intervention after ASO is not limited to a certain time frame but continues during adulthood. Santens etal13 reported a re-intervention rate of 21% at 20years in their retrospective long-term follow-up analysis, which is in contrast to the re-intervention rate of 28% at 20years in our study. However, this higher rate may be explained by our definition of RVOT interventions, which was not restricted to re-interventions at the pulmonary arteries but also included pulmonary valve replacements. In our study, the median age of the first RVOT re-intervention was 13.8years and is different than in other studies in which the age of first RVOT re-intervention varied between 9months and 3.8years,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 re-intervention at the LVOT was 7% at the age of 25years. This finding agrees with the results of a recent retrospective study by Fricke et al10 who reported a freedom from neo-aortic re-intervention of 92% at 25years. As most of these patients underwent neo-aortic re-interventions during adulthood (median age 21.3years), 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 etal17 observed no further increase of neo-aortic root diameter 10years 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 0.63mm/year.18 In 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 35years 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 re-intervention at the coronary arteries appeared to be low. This low rate is in line with current literature on late coronary complications after ASO.19 Ofthe 7patients 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.20 In contrast to previous studies, we did not find a relationship betweencomplex TGA-subtype and coronary 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
The cumulative incidence of a first re-intervention after ASO was 60% at 40years, demonstrating the ongoing need for re-interventions after ASO. Long-term outcome after the age of 40years 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 speculate a re-intervention rate up to 90% at the age of 60years. Therefore, regular follow-up with focus on both RVOT and LVOT seems necessary.
Study Limitations
Surgical technique may impact the long-term outcome. As our patient population included a nationwide TGA-ASO cohort, encompassing patients from different centers, we could not account for differences in surgical approaches between centers and surgeons. Although this enhances the external validity. Furthermore, analysis was performed with data extracted from 2 different registries, including the Concor registry (inclusion of adult patients since 2001) and the KinCor registry (inclusion of pediatric patients since 2013). Procedures which were performed before the ASO differed significantly between the 2 data sources and could be explained by the inclusion of patients from both centuries. Current analysis was not adjusted for multiple testing; therefore, CIs should be interpreted with caution. Our risk factor analysis was restricted to the available patient characteristics from the national registries, for example, details on coronary anatomy or ventricular function could not be taken into account as this was not available in the registry database.
Conclusions
Our study shows that TGA patients who survived the ASO have an excellent late survival of 93% at 35years. However, a significant number of patients required re-intervention especially at the RVOT and LVOTduring lifetime. 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.
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: TGA patients who survived the arterial switch operation have an excellent late survival (93%) at 35years. However, a significant number of patients required re-intervention at the RVOT and LVOT during lifetime. The number of coronary re-interventions and coronary events appeared to be very low.
TRANSLATIONAL OUTLOOK: 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. Therefore, regular follow-up with focus on both RVOT and LVOT seems recommended.
Central Illustration
Clinical Course of TGA After ASO: Mortality and Re-Intervention Rates at 35 Years
The figure demonstrates the clinical course of TGA after ASO at the age of 35year. The mortality and re-intervention rates represents the calculated cumulative incidence at the age of 35years for RVOT re-intervention, LVOT re-intervention, coronary artery re-intervention and death. The dotted line (and question mark) reflects the period after 35years, in which the outcome is still unknown. ASO=arterial switch operation; LVOT=left ventricular outflow tract; RVOT=right ventricular outflow tract.
Funding support and author disclosures
Support 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.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For supplemental tables and figures, please see the online version of this paper.
Supplementary data
Supplemental Figure1 and Table1:
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