Impact of pulmonary valve replacement on left ventricular rotational mechanics in repaired tetralogy of Fallot

In this single center study, rTOF subjects were retrospectively identified who met the following inclusion criteria: (1) had a CMR both ≤ 1 year before surgical PVR and ≤ 5 years after surgical PVR performed at Boston Children’s Hospital since January 1, 2002, (2) had no other intervening cardiac procedure between CMRs, (3) had predominantly volume loading (TOF-PR) or pressure loading (TOF-RVOTO) physiology at the time of PVR, (4) had a body surface area (BSA) > 1.0 m² at the time of the first CMR, and (5) had CMR images suitable for feature tracking (FT) analysis. Patients with TOF-PR physiology were defined as having a PR fraction > 40% and a right ventricular (RV) outflow tract (RVOT) peak gradient by echocardiography ≤ 25 mm Hg and patients with TOF-RVOTO physiology were defined as having a PR fraction ≤ 30% and a RVOT peak gradient or TR peak gradient ≥ 40 mm Hg by echocardiography. Similar grouping criteria for rTOF patients have been used in prior publications [32‐34]. These subgroups were predefined to permit an analysis of whether the impact of PVR on rotational mechanics differed between the two most common physiologies. Subjects were restricted to BSA > 1.0 m² to avoid including a large range of heart sizes which could produce a confounding effect on torsion metrics and to analyze a cohort of patients undergoing PVR at the most common time-in late childhood and adulthood. Age and sex matched controls were identified who had a CMR at Boston Children’s Hospital interpreted as normal, and who had no systemic or genetic disease with cardiovascular impact. A statistical power analysis was performed for sample size estimation based on preliminary data showing that the standard deviation of the change in torsion after PVR was 0.44 deg/cm. Using a two-sided, α = 0.05 level one-sample test of the null hypothesis that the mean absolute change in torsion was 0, the projected sample size required to detect a mean change in torsion as small as 0.22 deg/cm (one-half standard deviation) with 80% power was 32 patients. Given that the standard deviation was based on preliminary data and in order to ensure adequate power, we aimed to have 60 rTOF subjects. These 60 subjects were randomly selected from patients meeting the inclusion criteria. We matched the rTOF subjects with 30 controls, a 2:1 matching strategy driven by the limited availability of age and sex matched control subjects who had undergone a CMR using the same technique as the rTOF subjects.

For the rTOF subjects, data were abstracted from the medical record and included age at initial TOF repair, type of TOF repair, total number of cardiac surgeries, age at PVR, total number of PVRs, age at CMR, electrocardiographic (ECG) QRS duration at the time of CMR, and the results of echocardiograms performed within 12 months of each CMR. The Committee for Clinical Investigation at Boston Children’s Hospital approved this study and waived the requirement for informed consent.

The CMR protocol used for patients with rTOF has been previously published [35]. Briefly, all CMRs were performed on a 1.5 T CMR scanner (Achieva, Phillips Healthcare, Best, the Netherlands) using surface coils selected based on patient size. Imaging included a 12–14 slice stack (slice thickness 8–10 mm) of breath-hold, ECG-gated, balanced steady-state free precession (bSSFP) cine acquisitions in the short-axis plane to completely cover both ventricles. Twenty images per cardiac cycle were acquired and reconstructed to 30 images per cardiac cycle. ECG-gated phase contrast flow measurements were performed in the main pulmonary artery. Ventricular volumes and blood flow were measured using commercially available software (cvi42, Circle Cardiovascular Imaging Inc., Calgary, Alberta, Canada; and QMass, Medis Medical Imaging Systems, Leiden, the Netherlands).

LV rotational mechanics were measured by performing FT analysis on the short-axis bSSFP cine images using commercially available software (cvi42, Circle Cardiovascular Imaging). FT is an image processing technology that quantifies myocardial tissue deformation [36]. LV endocardial and epicardial contours were manually drawn at end-systole for all slices from the apex to base of the LV and were propagated by the software through the remaining phases. In cases of poor tracking, the contours were manually adjusted. The apical slice was defined as the most apical slice with blood pool throughout the entire cardiac cycle. The basal slice was defined as the most basal slice with a full rim of myocardium throughout the entire cardiac cycle. The length of the LV was defined as the distance between the apical and basal slice. The following parameters were assessed: direction of rotation (clockwise or counterclockwise), degrees of apical and basal rotation, rate of peak systolic and diastolic apical and basal rotation, peak systolic twist (synchronous apical−basal rotation), peak systolic torsion, and peak systolic and diastolic rate of torsion (Fig. 1). Peak systolic torsion was calculated using 2 methods: (1) twist divided by LV length and (2) calculating the gradient of twist down the long-axis of the LV by finding the slope of the linear regression line between twist and longitudinal position [37]. End-systolic torsion was also calculated by the second method. As there was no significant difference in torsion between the methods, data is only presented for the peak systolic torsion calculated as the twist divided by LV length. The timing of all events was expressed as a percentage of the LV systolic duration. The beginning of systole was defined as phase 0 (0% of LV systolic duration) and end-systole was defined as the phase with the smallest LV volume (100% of LV systolic duration). Rotation was defined as positive if there was counterclockwise rotation when viewing the short-axis image from the apex. Intraobserver variability of the LV rotational parameters was assessed by repeated measurement of approximately 15% of the total studies by the primary observer (J.K.H). Analysis was performed 4 weeks after the primary assessment to limit recall bias. Interobserver variability was assessed in these same studies by a second observer (N.T.).

Data are presented as mean ± standard deviation or median with interquartile range (IQR) as appropriate for continuous variables and as frequency (percentage) for categorical variables. A Student’s t-test was performed for mean comparisons between the rTOF and healthy control groups and between the rTOF patients with differing physiology. A Fisher exact test was performed for comparisons of categorical variables. Analysis of variance (ANOVA) was conducted for mean comparisons among 3 groups. If there was a significant 3-group difference, the p-value was adjusted for pairwise comparisons using the Tukey adjustment for multiple comparisons. The Benjamini–Hochberg false discovery rate method was applied to the total set of statistical tests performed for this study. A two-sided one sample t-test was used to assess whether the mean change in CMR and echocardiographic parameters between the first and second CMR was different from 0. The Pearson correlation coefficient was used to assess the correlation of clinical measures with peak torsion. Intra- and interobserver reproducibility were evaluated by estimation of the intraclass correlation coefficient (ICC). A p-value of ≤ 0.05 was considered statistically significant. Statistical analyses were performed using SAS (version 9.4, SAS Institute, Inc., Cary, North Carolina, USA) and R (version 3.2.1, R Foundation for Statistical Computing, Vienna, Austria).

There were 60 rTOF patients (23.6 ± 7.9 years, 52% male) and 30 controls (20.8 ± 3.1 years, 50% male). Their demographic and clinical information are presented in Table 1. At birth, 44 (73%) of the rTOF patients had pulmonary stenosis and 16 (27%) had pulmonary atresia. Additional anatomic features are listed in Table 1. The majority of the rTOF patients had a transannular patch repair (57%). The mean age at surgical repair was 2.1 ± 3.6 years. The median time between the pre-PVR CMR and PVR was 0.25 years (IQR: 3 days, 0.38 years), and the median time between the PVR and the post-PVR CMR was 1.00 years (IQR: 0.54, 1.74 years). There were significant differences in the type of TOF repair, number of surgeries, and number of PVRs between the TOF-PR and TOF-RVOTO subgroups (Table 1). The CMR indications for the control patients were suspected arrhythmogenic right ventricular cardiomyopathy (n = 18), family history of cardiomyopathy (n = 7), family history of a bicuspid aortic valve (n = 2), and other (n = 3). The patients with possible cardiomyopathy had a normal CMR as well as normal clinical and genetic evaluations.

The conventional CMR and echocardiographic parameters for the rTOF patients and the healthy controls are presented in Table 2. The rTOF patients had larger RV volumes and mass and lower RV ejection fraction (RVEF) and LVEF on their pre-PVR CMR compared with healthy controls. After PVR in the rTOF patients, RV volumes, RV mass, PR fraction, and RVOT peak gradient significantly decreased. There was not a significant change in the RVEF or LVEF after PVR.

The rotational mechanics from the CMR FT analysis for the rTOF patients and healthy controls are presented in Table 3 and Fig. 2 (and Additional file 1: Table S1). Compared with healthy controls, pre-PVR rTOF patients had significantly lower apical and basal rotation, twist, torsion, and systolic rotation rates, and apical rotation and torsion peaked earlier in systole. All of the healthy control patients had counterclockwise apical rotation and clockwise basal rotation, a normal pattern reported by others [38, 39]. There were two predominant rotational patterns seen in the rTOF cohort (Fig. 3). The majority of the rTOF patients (58%) had counterclockwise apical rotation and clockwise basal rotation (normal directions), but frequently the degree of rotation of the base and/or apex was reduced (Fig. 3b). The second most common pattern in the rTOF patients (32%) was reversed basal rotation and normal apical rotation direction (Fig. 3c).

In the rTOF patients, nearly all of the LV rotational parameters had no significant change following PVR (Table 3 and Fig. 4; and Additional file 1: Table S1). Of the 60 patients, only 16 patients (27%) showed an increase in torsion of > 0.5 deg/cm. The only rotational parameter that showed a significant change after PVR was the timing of peak torsion (Additional file 1: Table S1). After PVR, torsion peaked later in systole in the rTOF patients, closer to controls. After PVR, the number of patients with normal apical and basal rotation direction increased from 58 to 73%.

Two subgroups of rTOF patients were compared: patients with predominantly volume-loaded physiology (TOF-PR) (n = 38) and patients with predominantly pressure-loaded physiology (TOF-RVOTO) (n = 22) at the time of PVR (Table 4 and Additional file 1: Table S2). On the pre-PVR CMR, there were no significant differences between the two groups in the apical or basal rotation, twist, torsion, or rotation rates. However, apical rotation, apical systolic rotation rate, and torsion peaks occurred later in systole in the TOF-PR group. In both groups following PVR, there were no significant changes in the apical rotation, basal rotation, twist, or torsion.

Additional analyses focused on torsion in the rTOF patients at the time of their pre-PVR CMR. There was no significant difference between the 34 patients repaired at < 1 year of age and the 26 patients repaired at ≥ 1 year of age (1.01 ± 0.63 versus 0.75 ± 0.66, p = 0.13), between the 18 patients with a staged repair and the 42 patients with a primary complete repair (0.80 ± 0.76 versus 0.94 ± 0.60, p = 0.44), or between the 31 patients repaired before 1990 and the 29 patients repaired in or after 1990 (0.89 ± 0.49 versus 0.91 ± 0.80, p = 0.94).

The intra- and interobserver reproducibility (n = 15) for peak systolic torsion as measured by the ICC were good (0.80, 95% CI 0.50, 0.93) and moderate (0.65, 95% CI 0.25, 0.87), respectively.

Table 5 reports the correlation between peak systolic torsion prior to PVR and clinical, CMR, and echocardiographic parameters in the rTOF group. Among all of these, only a weak correlation of peak torsion with RV end-systolic volume index (RVESVI) and with RVEF was detected. Late gadolinium enhancement of the LV and/or RV myocardium, beyond the common enhancement at the septal insertions, anterior infundibular free wall, and ventricular septal defect patch, was rare in this cohort (4 pre-PVR CMR studies) and was not included in the correlation analysis.