Patients with tetralogy of Fallot and combined right ventricular outflow tract obstruction (RVOTO) and pulmonary regurgitation (PR) have a less dilated right ventricular (RV) and better RV function compared with patients without RVOTO. It is not known whether RVOTO is associated with improved exercise capacity. We compared cardiac magnetic resonance imaging, echocardiography, and exercise tests in 12 patients with RVOTO (Doppler peak RVOT gradient ≥30 mm Hg) and 30 patients without RVOTO. RV end-systolic and end-diastolic volumes were smaller in patients with RVOTO compared with patients without RVOTO (50 ± 16 vs 64 ± 18 ml/m 2 and 117 ± 24 vs 135 ± 28 ml/m 2 , respectively) and patients with RVOTO had a higher RV mass (52 ± 14 vs 42 ± 11 ml/m 2 ), p <0.05. RV ejection fraction was marginally significantly different between both groups (58 ± 8% vs 53 ± 7%), p = 0.051. Degree of PR, left ventricular volumes, and function did not differ significantly between both groups. Peak oxygen uptake in patients with RVOTO was significantly lower (25 ± 3 vs 32 ± 8 ml/kg/min) than in patients without RVOTO, as was the percentage of predicted peak oxygen uptake (63 ± 7% vs 79 ± 14%), p <0.001. Multivariate analysis showed that the peak RVOT gradient was the only independent predictor of exercise capacity. In conclusion, exercise capacity is lower in patients with RVOTO compared with those without RVOTO despite a less dilated RV and comparable degree of PR. Therefore, exercise capacity may be of importance and should additionally be taken in consideration to RV volumes and function in patients with tetralogy of Fallot and PR.
Most adult patients with repaired tetralogy of Fallot (ToF) have longstanding pulmonary regurgitation (PR). PR results in chronic right ventricular (RV) volume overload and has been related to RV dilation, RV dysfunction, symptomatic heart failure, ventricular arrhythmia, and sudden death. In addition to PR, many patients have residual RVOTO resulting in some pressure overload. Animal studies have demonstrated that RVOTO may limit the negative impact of PR on RV size and myocardial contractility. However, the increase in cardiac output during dobutamine infusion did not differ between animals with PR and animals with combined RVOTO and PR. This suggests that despite smaller RV volumes with higher myocardial contractility, patients with combined RVOTO and PR do not have better exercise capacity than patients with isolated PR. Indeed, New York Heart Association functional class of patients with combined RVOTO and PR did not differ compared with patients with isolated PR despite smaller RV size in patients with ToF and combined RVOTO and PR. However, because functional class is known to be poorly correlated with objective exercise capacity, it remains unclear which effect RVOTO has on exercise capacity. Therefore, we evaluated the effects of RVOTO on exercise capacity, RV volumes, and RV function in adult patients with repaired ToF and volume overload because of PR.
Methods
This retrospective study was approved by the University Medical Center Groningen review board. Informed consent was not required according to the Dutch Medical Research Involving Human Subjects act.
Our institute’s cardiac magnetic resonance (CMR) imaging database contained 123 patients with repaired ToF without a pulmonary valve replacement. We included data of patients who underwent adequate echocardiographic examination, exercise testing, and CMR imaging in a time span of 6 months (n = 48; 39%) and in whom no clinical relevant event occurred in the meantime. All examinations were part of routine follow-up in our center. Patients with significant regurgitation or stenosis of other valves than the pulmonary valve and residual intracardiac shunts were excluded (n = 6). The remaining 42 patients were divided into 2 groups: 12 patients with combined PR and RVOTO and 30 patients with PR without RVOTO. RVOTO was defined as a Doppler peak pressure gradient across the RVOT >30 mm Hg.
All subjects were examined on a 1.5-T MRI system (Siemens Magnetom Sonata, Erlangen, Germany, or Siemens Magnetom Avanto, Erlangen, Germany) using a 2 × 6-channel body coil. After single-shot localizer images, short-axis cine loop images with breath holding in expiration were acquired using a retrospectively gated balanced steady-state–free precession sequence. The following parameters were used: repetition time 2.7 ms, echo time 1.1 ms, flip angle 80°, matrix 192 × 192 mm, 25 frames per cycle, slice thickness 6 mm, interslice gap 4 mm, and voxel size 1.7 × 1.7 × 6 mm.
Two-dimensional velocity-encoded MRI flow measurements perpendicular and directly cranial to the pulmonary valve were performed to quantify flow velocity and volumes.
Analysis of CMR images has been described previously. In summary, image analysis was performed semiautomatically by using QMass MR research edition (Medis, Leiden, The Netherlands). Left ventricular (LV) and RV contours were drawn manually by tracing the endo- and epicardial borders in every slice in the end-systolic and end-diastolic frame. The end-systolic phase of the RV was selected independently from the LV. Papillary muscles and trabeculae were excluded from the RV blood volume and included in the mass. Stroke volume was calculated by subtracting the end-systolic volume from the end-diastolic volume. The ejection fraction was obtained by dividing stroke volume by end-diastolic volume. Analysis of MRI flow measurements was performed using QFlow version 5.2 (Medis). Contours were drawn manually in all 30 phases. PR was quantified as PR fraction and PR volume. All ventricular volumes were indexed for body surface area.
Continuous-wave Doppler was used to determine the maximum velocity across the RV outflow tract. The RV outflow tract gradient was calculated using the simplified Bernoulli equation. The presence of restrictive physiology was defined as forward flow across the pulmonary valve during 3 consecutive cycles in end-diastole. The tricuspid and left-sided valves were reviewed for significant stenosis or regurgitation. All patients were screened for the presence of residual intracardiac shunts.
All patients performed a treadmill cardiopulmonary exercise test. Workload was incremented at regular intervals with a combination of speed and inclination. A modified Bruce protocol was used in which workload starts at a relatively low level and increases more gradually than in the standard Bruce protocol. In the first stage, speed was 1.7 miles/hour and incline 0%; in the second stage, the same speed and 5% incline, and the third stage corresponded to the first stage of the Bruce protocol. Cardiopulmonary exercise testing ended when patients reached their peak oxygen uptake (VO 2 ), could not keep up with the treadmill speed, breathing reserve and O 2 heart rate decreased, or when discontinuation was indicated for safety reasons. Peak VO 2 was calculated as the average VO 2 for the 2 highest measurements at peak exercise and expressed as milliliters per minute per kilogram and as percentage of predicted maximum VO 2 . Respiratory exchange ratio was computed as carbon dioxide production/VO 2 . Exercise tests were only included when the patient reached the anaerobic threshold, defined as having a respiratory exchange ratio >1.0.
Descriptive statistics were calculated for all measurements as mean and SD for normally distributed continuous variables, median with twenty-fifth and seventy-fifth percentile for skewed continuous variables, and absolute numbers and percentages for dichotomous variables. Differences in characteristics between patient groups were analyzed using Student’s t test for normally distributed continuous variables and Mann-Whitney U test for skewed continuous variables. Fisher’s exact test was used for comparison of categorized variables. Univariate linear regression analysis was performed to determine which variables were significantly related to percentage of predicted peak VO 2 . Variables included were patient characteristics (age at exercise testing, gender), operative characteristics (age at repair, usage of transannular patch), imaging parameters (CMR measurements of RV volume and function and LV function, degree of PR on CMR, presence of restrictive physiology and peak pressure gradient across the RVOT), and QRS duration. In multivariate analysis, we evaluated independent predictors of peak VO 2 . Only variables statistically significant (p <0.050) in univariate analysis were included in the multivariate analysis (backward stepwise regression method). The Statistical Package for the Social Sciences version 20.0 (SPSS Inc, Chicago, IL) was used for all statistical analyses. All statistical tests were 2 sided and a p value <0.050 was considered to be statistically significant.
Results
Patient characteristics did not differ significantly between both groups except for peak gradient across the RVOT ( Table 1 ). Significantly smaller RV end-systolic and end-diastolic volumes and higher RV mass were observed in patients with combined RVOTO and PR than in patients with isolated PR, p <0.050. There was a trend toward a higher RV ejection fraction in patients with combined RVOTO and PR compared with patients with isolated PR, p = 0.051. Severity of PR; LV end-systolic, end-diastolic, and stroke volumes; and LV ejection fraction were not significantly different between both groups ( Table 2 ).
| Variable | All Patients (42) | Isolated PR (n = 30) | Combined RVOTO and PR (n = 12) | p |
|---|---|---|---|---|
| Male | 25 (60%) | 15 (50%) | 10 (83%) | 0.081 |
| Age at repair (yrs) | 2.7 (1.3–5.7) | 2.5 (1.3–5.5) | 3.9 (1.8–5.9) | 0.449 |
| Age at study (yrs) | 32 ± 9 | 30 ± 9 | 34 ± 9 | 0.246 |
| Previous palliative shunt | 9 (21%) | 6 (20%) | 3 (25%) | 0.699 |
| Transannular patch | 22/41 (54%) | 14 (47%) | 8/11 (73%) | 0.173 |
| New York Heart Association | 1.000 | |||
| Functional class | ||||
| Class I | 41 (98%) | 29 (97%) | 12 (100%) | |
| Class II | 1 (2%) | 1 (3%) | 0 (0%) | |
| RV outflow tract peak gradient (mm Hg) | 24 ± 14 | 16 ± 6 | 42 ± 9 | <0.001 |
| Restrictive physiology | 14/38 (37%) | 10/27 (37%) | 4/11 (36%) | 1.000 |
| QRS duration (ms) | 136 ± 26 | 137 ± 26 | 132 ± 30 | 0.579 |
| Variable | All Patients (42) | Isolated PR (n = 30) | Combined RVOTO and PR (n = 12) | p |
|---|---|---|---|---|
| Pulmonary regurgitation (%) | 36 ± 15 | 34 ± 15 | 38 ± 16 | 0.456 |
| Pulmonary regurgitation >20% | 36 (86%) | 25 (83%) | 11 (92%) | 0.655 |
| Pulmonary regurgitation volume (ml/m 2 ) | 26 ± 15 | 26 ± 14 | 27 ± 17 | 0.820 |
| RV end-systolic volume (ml/m 2 ) | 60 ± 18 | 64 ± 18 | 50 ± 16 | 0.021 |
| RV end-diastolic volume (ml/m 2 ) | 130 ± 28 | 135 ± 28 | 117 ± 24 | 0.049 |
| RV stroke volume (ml/m 2 ) | 70 ± 15 | 71 ± 15 | 67 ± 14 | 0.448 |
| RV ejection fraction (%) | 54 ± 7 | 53 ± 7 | 58 ± 8 | 0.051 |
| RV mass (ml/m 2 ) | 45 ± 13 | 42 ± 11 | 52 ± 14 | 0.019 |
| LV end-systolic volume (ml/m 2 ) | 38 ± 9 | 39 ± 8 | 37 ± 10 | 0.552 |
| LV end-diastolic volume (ml/m 2 ) | 87 ± 13 | 88 ± 12 | 84 ± 13 | 0.398 |
| LV stroke volume (ml/m 2 ) | 48 ± 7 | 49 ± 8 | 47 ± 6 | 0.483 |
| LV ejection fraction (%) | 56 ± 6 | 56 ± 6 | 57 ± 6 | 0.674 |
| LV mass (ml/m 2 ) | 53 ± 8 | 52 ± 8 | 55 ± 8 | 0.174 |
Mean time between CMR and exercise testing was 1.9 ± 7.6 weeks. Patients with combined RVOTO and PR showed a significantly lower percentage of predicted peak VO 2 than patients with isolated PR, p <0.001. Exercise capacity was impaired, defined as peak VO 2 <85% of the predicted value, in all patients with combined RVOTO and PR and in 20 (67%) patients with isolated PR, p = 0.040. Heart rate at rest did not differ significantly between both groups. The lower maximum heart rate and lower percentage of predicted maximum heart rate in patients with combined RVOTO and PR compared with patients with isolated PR were not statistically significant ( Table 3 ). Univariate analysis showed a statistically significant relation between percentage of predicted peak VO 2 and peak pressure gradient across the RVOT ( Figure 1 ) and RV end-diastolic volume. In multivariate analysis, the peak pressure gradient across the RVOT was the only independent predictor of exercise capacity ( Table 4 ).
