Our aim was to assess changes of right ventricular end-diastolic volumes (RVEDVi) and right ventricular ejection fraction (RVEF) in asymptomatic adults with repaired tetralogy of Fallot, with native right ventricular outflow tract and severe pulmonary regurgitation by serial cardiac magnetic resonance imaging (CMR). The study included 23 asymptomatic adults who underwent ≥3 CMR studies (total of 88 CMR studies). We compared changes in RVEDVi and RVEF between first and last study (median follow-up: 8.8 years, interquartile range: 6.3 to 13.1 years) and between all study pairs. Variability of measurements between study pairs (65 consecutive and 139 nonconsecutive CMR study pairs) were assessed using Bland–Altman analysis and intraclass correlation coefficients. On average, there were no significant changes of RVEDVi or RVEF over the study period (change in RVEDVi: +0.4 ± 17.8 ml/m 2 , change in RVEF: −1.0 ± 5.5%). Assessment of variability of measurements between study pairs demonstrated no systematic change in RVEDVi and RVEF between study pairs with limits of agreement within the range of previously published studies (RVEDVi −29.1 to +27.2 ml/m 2 ; RVEF −11.5% to 10.2%). High intraclass correlation coefficients for RVEDVi (0.943, 95% CI 0.906 to 0.965, p <0.001) and RVEF (0.815, 95% CI 0.697 to 0.887, p <0.0001) indicate high reliability of reported measurements. In conclusion, in asymptomatic adults with repaired tetralogy of Fallot with native right ventricular outflow tracts and severe pulmonary regurgitation, CMR measurements of RV volumes and RVEF remain stable during follow-up with variability between CMR studies in individual patients, as expected for interobserver and interstudy variability. Measurements derived from a single CMR study or changes occurring between 2 CMR studies should be used with caution for clinical decision-making.
Severe pulmonary regurgitation is the most prevalent residual lesion after childhood repair of tetralogy of Fallot. In some retrospective studies, an association between the presence of residual pulmonary regurgitation with adverse outcomes was observed. Cardiac magnetic resonance imaging (CMR) has emerged as the reference method for measurements of right ventricular volumes and function. Based on CMR studies, European and North American guidelines for the management of adults with congenital heart disease recommend specific thresholds of right ventricular volumes and function (right ventricular end-diastolic volumes [RVEDVi] of ≥160 ml/m 2 , right ventricular end-systolic volume [RVESVi] ≥80 ml/m 2 , right ventricular ejection fraction [RVEF] <45%) for prosthetic pulmonary valve replacement in asymptomatic adults with repaired tetralogy of Fallot. , Although there is a general belief that right ventricular dilatation and dysfunction are progressive in nature, only a few studies have actually analyzed its evolution using cardiac magnetic resonance imaging. The aim of this study was to analyze changes in right ventricular volumes and function in clinically stable, asymptomatic adults with repaired tetralogy of Fallot with native right ventricular outflow tracts and residual severe pulmonary regurgitation using serial CMR imaging.
Methods
From the Swiss SACHER-registry ( ClinicalTrials.gov Identifier NCT 2,258,724), we identified asymptomatic adults with repaired tetralogy of Fallot; severe residual pulmonary regurgitation and a native right ventricular outflow tract; followed at the university hospitals of Basel, Berne, and Zurich (CMRs performed at the University Children’s hospital); who had undergone ≥3 CMR studies during adulthood; without any interventions, endocarditis, or arrhythmias between studies. Only patients with pure pulmonary regurgitation without concomitant right ventricular outflow tract obstruction were included. The registry was approved by the local ethics committee (BASEC: 2019-01935) and all patients had given written informed consent for analysis of clinical data at the time of enrollment into the registry. The study complies with the Declaration of Helsinki. Baseline patient characteristics and results from cardiac magnetic resonance imaging were derived from chart review. The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
All CMR studies had been performed on clinical indication as part of routine follow-up as recommended in guidelines. , All CMR studies followed previously published protocols and were performed and analyzed at each center by the same dedicated specialist teams with extensive experience in the field. Severe pulmonary regurgitation was defined as pulmonary regurgitation fraction >30% on cardiac magnetic resonance imaging as suggested by guidelines. Impaired right ventricular systolic function was defined as an RVEF <45%. ,
Clinical decision making in asymptomatic adults with repaired tetralogy of Fallot is based on ventricular dimensions indexed to body surface area. For the purpose of this study, measurements of RVEDVi, indexed to body surface area; RVESVi, indexed to body surface area; RVEF; and pulmonary regurgitant fraction were abstracted from clinical CMR reports. Interobserver variability was tested with blinded re-analysis of 30 CMR studies (15 study pairs) by a CMR specialist of a different study center.
We compared changes in RVEDVi and RVEF between the first and the last CMR study for the entire cohort and between all pairs of CMR studies in individual patients.
Interobserver and interstudy variabilities between CMR studies were assessed using the methods described by Bland and Altman and by estimation of intraclass correlation coefficients (ICC).
Statistical analysis was performed using SPSS version 26.0 (SPSS, Inc., Chicago, Illinois). Descriptive data are presented as median (range or interquartile range), mean ± standard deviation, and proportions, as appropriate. For comparisons between average measurements of right ventricular dimensions and function, and biometric data, paired t tests or related samples Wilcoxon tests were used, as appropriate. For comparison between groups, chi-square of Fischer’s exact tests were used, as appropriate. Interobserver variability and interstudy variability were investigated as described by Bland and Altman and by calculating ICC estimated with variance components models. Agreement for each measurement (limits of agreement) was expressed as 2 standard deviations of the interstudy differences. ICC estimates and their 95% confidence intervals (CI) were calculated using SPSS statistical package version 26 (SPSS Inc, Chicago, Illinois) based on a mean-rating, absolute-agreement, 2-way mixed-effects model. The ICC indicates the proportion of variability explained by real changes of measurements as opposed to interstudy variability, observer differences, or random error. A p value <0.05 (2-sided) was considered statistically significant.
Results
Of all adults with repaired tetralogy of Fallot followed at the participating centers, 235 had undergone at least 1 CMR study. Of these, 77/235 had a native right ventricular outflow tract (33%) (i.e., without previous conduit or bioprosthesis implantation) with severe pulmonary regurgitation (defined as a regurgitation fraction ≥30%). Of these 77 patients, 41 patients had serial CMR studies and 23 patients had at least 3 complete consecutive CMR studies (range: 3 to 7 studies). These 23 patients were included in the study group. This allowed analysis of a total of 88 CMR studies amounting to 65 pairs of consecutive CMR studies and a total of 139 consecutive and nonconsecutive study pairs (e.g., comparison of first study with third CMR study, second CMR study with fourth CMR study, and so on). Median age at first CMR was 26.1 years (IQR: 19.9 to 38.2 years) and median follow-up duration was 8.8 years (IQR: 6.3 to 13.1 years). Within the study cohort, 15 patients (65%) were women. A total of 9 patients had undergone a palliative procedure (39%) before intracardiac repair. Intracardiac repair had been performed at a median age of 3.8 years (IQR: 2.4 to 49 years). A total of 19 patients (83%) had undergone transannular patch repair. All patients had native pulmonary outflow tracts without previous conduit or bioprosthesis implantation. None of the patients had any degree of right ventricular outflow tract obstruction. All patients were in sinus rhythm. None of the patients had a sustained atrial or ventricular arrhythmia, infective endocarditis, or new onset heart failure over the study period.
For the entire study cohort, illustrated in Table 1 , there were no significant changes in right ventricular volumes, right ventricular ejection fraction, and pulmonary regurgitant fraction over the study period. This was also true for all 41 patients with serial CMR studies analyzed (RVEDVi on first versus last CMR study: 153.4 ± 32.4 versus 153.4 ± 28 ml/m 2 , p = 0.98; RVEF on first versus last CMR study: 47.6 ± 7.7 versus 47.7 ± 7.5%, p = 0.85). Among the 23 patients within the study cohort, there was a small, albeit statistically significant, average increase in body weight over the study period, corresponding to a small increase in body surface area. In addition, there was a small increase of average heart rate. Over the entire study period, 15 patients (65%) fulfilled at least once the indication for pulmonary valve replacement according to the North American guidelines and 16 patients (70%) according to the European guidelines. In 2/15 patients (13%) meeting the North American guidelines criteria for pulmonary valve replacement and in 1/16 patients (6%) meeting the European guidelines criteria, measurements of right ventricular volumes decreased and/or RVEF increased during follow-up to the point that patients no longer met guidelines criteria for intervention.
| Baseline CMR | Last CMR | p Value | |
|---|---|---|---|
| RVEDVi (ml/m 2 ) | 158.1±30.7 | 158.7±29.1 | 0.890 |
| RVESVi (ml/m 2 ) | 81.4±24.1 | 83.6±24.6 | 0.457 |
| RVEF (%) | 49.1±7.8 | 48.1±8.2 | 0.394 |
| Pulmonary regurgitant fraction (%) | 43.4±13.6 | 43.5±7.4 | 0.956 |
| Weight (kg) | 65.5±13.9 | 70.4±13.5 | 0.001 |
| Body surface area (m 2 ) | 1.73±0.19 | 1.80±0.18 | 0.001 |
| Heart rate (beats / minute) | 73±9 | 79±9 | 0.047 |
On average, there were no significant changes of RVEDVi, RVESVi, RVEF, or pulmonary regurgitation fraction over the follow-up duration of more than 8 years. There were, however, large deviations (both increasing and decreasing values) between individual study pairs. This translates into merely absent average absolute changes in RVEDVi (+0.4 ± 17.8 ml/m 2 ), RVESVi (+2.1 ± 13.5 ml/m 2 ), RVEF (−1.0 ± 5.5%), and pulmonary regurgitation fraction (+0.1 ± 11.3%) with relatively large standard deviations, reflecting variability of measurements (p >0.1 for all comparisons).
Although average right ventricular volumes remained stable within the entire study cohort, variability of RVEDVi between study pairs in individual patients were large, as illustrated in Figure 1. Among the 65 consecutive study pairs, an increase in RVEDVi was observed in 33 study pairs (51%), a decrease in 29 study pairs (45%), and no change in 3 study pairs (5%) ( Figure 1 ). A total of 5 patients (22%) with an RVEDVi ≥160 ml/m 2 at some point during follow-up had regression of RVEDVi to <160 ml/m 2 on subsequent CMR studies ( Figure 1 ).
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