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Published online before print February 21, 2002, 10.1148/radiol.2231010924
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(Radiology 2002;223:204-211.)
© RSNA, 2002

Cardiac Imaging

Exercise MR Imaging in the Assessment of Pulmonary Regurgitation and Biventricular Function in Patients after Tetralogy of Fallot Repair1

Arno A. W. Roest, MSc, Willem A. Helbing, MD2, Patrik Kunz, PhD, Joost G. van den Aardweg, MD, Hildo J. Lamb, PhD, Hubert W. Vliegen, MD, Ernst E. van der Wall, MD and Albert de Roos, MD

1 From the Departments of Pediatric Cardiology (A.A.W.R., W.A.H.), Radiology (A.A.W.R., P.K., H.J.L., A.d.R.), Cardiology (A.A.W.R., H.W.V., E.E.v.d.W.), and Pulmonology (J.G.v.d.A.), Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands; and Interuniversity Cardiology Institute of the Netherlands, Utrecht (A.A.W.R., E.E.v.d.W., A.d.R.). Received May 14, 2001; revision requested June 15; revision received August 13; accepted September 28. Address correspondence to A.d.R. (e-mail: a.de_roos@lumc.nl).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To assess the responses of pulmonary regurgitation (PR) and biventricular function to submaximal exercise by using a magnetic resonance (MR) imaging exercise protocol with young adult patients who underwent tetralogy of Fallot repair at a young age.

MATERIALS AND METHODS: Fifteen patients with corrected tetralogy of Fallot (mean age, 17.5 years ± 2.5 [SD]) underwent MR imaging at rest and during exercise for the evaluation of PR and biventricular function. Results were compared with findings from 16 control subjects (mean age, 17.5 years ± 2.3). Mean age at tetralogy of Fallot repair was 2.1 years ± 1.6, and mean follow-up time after repair was 15.4 years ± 2.6. Exercise level at MR imaging was calculated individually and corresponded to 60% of peak oxygen uptake. The parameters of cardiac function obtained at rest and during exercise were compared by using a paired t test. An unpaired t test was used to compare parameters of cardiac function between patients and control subjects.

RESULTS: PR decreased during exercise (from 27 mL/m2 ± 17 to 23 mL/m2 ± 15; P = .012). At rest, right ventricular (RV) ejection fraction was normal (>47%) in 80% of patients. RV response to exercise in the patient group was abnormal compared with response in the control group, as demonstrated by an increase in RV end-diastolic volume index (132 mL/m2 ± 36 to 137 mL/m2 ± 38; P = .041) and no significant change in end-systolic volume index or ejection fraction. In only one patient, RV ejection fraction increased by more than 5%. Left ventricular response was not different between patients and control subjects.

CONCLUSION: MR imaging is well suited to assess cardiac response to exercise, and findings revealed a decrease in PR and an abnormal RV response to exercise in patients with corrected tetralogy of Fallot.

© RSNA, 2002

Index terms: Pulmonary arteries, flow dynamics, 564.91 • Pulmonary arteries, MR, 564.12144 • Tetralogy of Fallot, 51.145, 51.452


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Tetralogy of Fallot is one of the most common types of cyanotic congenital heart disease (1) and requires corrective surgery early in life. Although long-term survival rates are good (2), pulmonary regurgitation (PR), a common finding after primary correction (3), influences clinical outcomes of patients with corrected tetralogy of Fallot (4). Long-standing volume overload of the right ventricle (RV) is associated with biventricular dysfunction (5–7), ventricular arrhythmia (8), and impaired exercise capacity (9–12).

Evaluation of PR and biventricular function during exercise may reveal cardiac dysfunction that is not apparent at rest (13). Information on cardiac dysfunction is important for patient care and timing of pulmonary valve replacement after tetralogy of Fallot correction (14).

Quantitative assessment of PR during exercise has not been possible so far. Furthermore, noninvasive assessment of biventricular function at rest or during exercise is limited with the use of radionuclide angiography (15) or echocardiography (16).

Magnetic resonance (MR) imaging is an accepted and validated method for monitoring PR and biventricular function at rest in patients with corrected tetralogy of Fallot (17,18). Recently, exercise MR imaging was optimized to study cardiac function during supine submaximal bicycle exercise (19).

The goal of the present study was to assess the responses of PR and biventricular function to submaximal exercise by using an MR imaging exercise protocol with young adult patients who underwent tetralogy of Fallot repair at a young age.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients
Fifteen asymptomatic patients with corrected tetralogy of Fallot (age range, 14.3–23.5 years; mean age, 17.5 years ± 2.5 [SD]) were studied. These patients were scheduled to undergo cardiac MR imaging at rest for clinical follow-up of PR and biventricular function after total tetralogy of Fallot correction, and they did not have contraindications for MR imaging (such as the presence of a pacemaker, arrhythmia, or claustrophobia, or the inability to perform bicycle exercise). Findings were compared with those of 16 healthy control subjects (age range, 14.5–21.6 years; mean age, 17.5 years ± 2.3). The groups were matched for age, height, body weight, and body surface area (Table 1). The control subjects were healthy at clinical examination, showed normal electrocardiographic findings at rest, and had no history of cardiovascular disease and no symptoms.


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  		TABLE 1. Characteristics of Study Population

 
Mean patient age at tetralogy of Fallot correction was 2.1 years ± 1.6, and mean follow-up time after repair was 15.4 years ± 2.6. During follow-up after correction, no patient had clinically important atrioventricular or aortic valve regurgitation or residual intracardiac shunts on the basis of echocardiographic and standard MR imaging findings (7). Informed consent was obtained from all individuals, and the medical review board of Leiden University Medical Center approved the study.

Exercise Testing
Exercise testing was performed prior to MR imaging. A maximal exercise test was performed with the individual in the supine position on an MR-compatible bicycle ergometer (MR imaging cardiac ergometer; Lode, Groningen, the Netherlands). Each individual performed a 10-W/min protocol that involved exercising at increasing levels of difficulty until he or she was exhausted. Electrocardiograms were continuously recorded, and arterial oxygen saturation was monitored by using a pulse oximeter (model N200; Nellcor, Pleasanton, Calif). The following parameters were measured during the exercise test by using a gas analyzer (Oxycon Record; Jaeger, Höchberg, Germany): total ventilation, breathing frequency, oxygen uptake, and carbon dioxide release. Oxygen uptake was indexed to body weight. A respiratory exchange ratio (carbon dioxide release/oxygen uptake) was used as an indicator of anaerobic metabolism during exercise.

Forced expiratory volume in 1 second (FEV1) was measured before the exercise test with the individual in a sitting position. Maximal voluntary ventilation (MVV) was calculated (20) as FEV1 x 40. Subsequently, exercise breathing reserve, which was defined as the unused percentage of MVV at peak exercise (21), was evaluated ([1 - maximal ventilation/MVV] x 100). Normal breathing reserve was defined as more than 20% of maximal voluntary ventilation (9).

MR Imaging
MR imaging was performed by using a 1.5-T imager equipped with a Powertrak 6000 gradient system (ACS-NT15; Philips Medical Systems, Best, the Netherlands) and a CPR-6 cardiac research software package (Philips Medical Systems). After scout radiographs were obtained, MR flow velocity measurements with retrospective electrocardiographic gating were obtained at rest in the pulmonary trunk between the pulmonary valve and the pulmonary bifurcation, as previously described (7).

Furthermore, 10 consecutive images were obtained in the left ventricular (LV) short-axis orientation to allow visualization of the LV and the RV from apex to base. The short-axis images were obtained at rest and during exercise by using a turbo-field echo-planar imaging sequence with prospective electrocardiographic triggering. This sequence is a combination of k-space segmentation and echo-planar imaging that allows fast imaging with a short echo time. Two excitations per heartbeat were applied for each heart phase. Each excitation was followed by five echo-planar imaging readouts, which resulted in the recording of 10 lines in k space per heartbeat for each heart phase. During four heartbeats, k space was filled for all heart phases. This allowed imaging of one short-axis section in four heartbeats. Two short-axis images were acquired during a breath hold of eight cardiac cycles at end expiration.

Exercise was performed during MR imaging with the individual in the supine position on the MR-compatible ergometer. Exercise level for the examination was calculated individually on the basis of workload as it corresponded to 60% of the maximal oxygen uptake, which was measured during the preceding maximal exercise test. After reaching a steady heart rate, the individual performed a breath hold of eight cardiac cycles during an exercise break, and two short-axis images were obtained (Fig 1). After acquisition of the images, the individuals resumed cycling until the steady exercise heart rate was again reached. The breath-hold procedure was repeated up to five times to acquire a total of 10 short-axis MR images.



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  		Figure 1. Schematic description of the MR imaging examination protocol. At rest and during exercise, 10 consecutive short-axis images were obtained. Two short-axis images were obtained during a breath hold of eight cardiac cycles (). The individuals started cycling, and, after reaching a steady heart rate, they performed a breath hold of eight cardiac cycles during a short exercise break. After acquisition of the images, the individuals resumed cycling until the steady-state heart rate was again reached, and the breath-hold procedure was repeated. Exercise level during MR imaging was individually calculated on the basis of peak oxygen consumption, which was measured during the preceding maximal exercise test.

 
For the MR flow velocity measurements obtained in the pulmonary trunk, we used a section thickness of 8 mm and a field of view of 300 x 300 mm. The flip angle was 20°, the echo time was 12 msec, velocity encoding was 200 cm/sec, and temporal resolution was 30 msec. The 128 x 128 image matrix was reconstructed by using zero filling of k space to a 256 x 256 matrix.

For the turbo-field echo-planar short-axis imaging measurements, we used a section thickness of 10 mm with a 1-mm gap. Flip angle was 30°, echo time was 4.8 msec, and repetition time was 14 msec, resulting in a temporal resolution of 31 msec. Field of view was 420 x 210 mm with a 128 x 40 image matrix, which was reconstructed by using zero filling of k space to a 256 x 256 matrix.

Data Analysis
MR flow velocity measurements obtained in the pulmonary trunk were analyzed manually by one observer (A.A.W.R.) by using the FLOW software package (Medis, Leiden, the Netherlands) (22), which allowed calculation of PR volume and percentage of RV stroke volume (7). The amount of PR was compared between patients who underwent tetralogy of Fallot correction with and patients who underwent correction without the use of a patch for relief of pulmonary stenosis, regardless of position and extent of the patch (23). Restrictive RV filling was defined as diastolic forward flow in the pulmonary trunk that corresponded to right atrial contraction (24–26).

The short-axis images were analyzed manually by one observer (A.A.W.R.) with the MASS software package (Medis) (27). Quantitative analysis of the short-axis images allowed calculation of the following parameters for each ventricle: systolic time, diastolic time, end-diastolic volume, end-systolic volume, stroke volume, and ejection fraction. Abnormal RV ejection fraction at rest was defined as being less than 47% (-2 SD of normal value [28,29]). PR was also calculated on the basis of the short-axis measurements by subtracting LV stroke volume from RV stroke volume (17) and was expressed as a percentage of RV stroke volume. The change in PR from rest to exercise was evaluated on the basis of the short-axis images, assuming there was no exercise-induced atrioventricular or aortic valve regurgitation. Normal ventricular response to exercise was defined as an increase in ejection fraction of more than 5% (30). Cardiac volumes were indexed to body surface area. All data were expressed as mean ± SD.

Statistical Analysis
A paired t test was used to compare PR derived from the short-axis measurements obtained at rest with PR derived from the MR flow velocity measurements obtained at rest. The parameters of cardiac function obtained at rest and during exercise were compared by using a paired t test. Pearson correlation analysis was used to evaluate correlation between parameters. An unpaired t test was used to compare the mean parameter values for exercise performance and cardiac function between patients and control subjects. Level of significance was P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Exercise Testing
All individuals reached a respiratory exchange ratio of greater than 1.0 at peak exercise, indicating at least a near-maximal effort during the graded maximal exercise test (31). No difference in respiratory exchange ratio was observed between groups at peak exercise, indicating that individuals in both groups attained a comparable level of anaerobic metabolism (Table 2). All individuals recorded leg fatigue as the reason to stop exercising. At peak exercise, patients with corrected tetralogy of Fallot had a significantly lower oxygen uptake per kilogram of body weight than that of the control subjects (36 mL · min-1 · kg-1 ± 5 vs 39 mL · min-1 · kg-1 ± 5, respectively; P = .043), resulting in an exercise capacity of 91% in the control group. Furthermore, maximal achieved workload of patients was lower than that of control subjects (176 W ± 42 vs 215 W ± 47, respectively; P = .022).


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  		TABLE 2. Pulmonary Function at Peak Exercise

 
Heart rate at peak exercise was lower in the patient group than in the control group (165 beats per minute ± 16 vs 178 beats per minute ± 11, respectively; P = .013). Total ventilation and breathing frequency at peak exercise did not differ between the two groups (Table 2). Fourteen patients had a normal breathing reserve, and no significant difference in breathing reserve was observed between groups (Table 2).

PR and Biventricular Function at Rest
PR volume index and PR percentage at rest as calculated from the short-axis measurements were 27 mL/m2 ± 17 and 35% ± 20, respectively. These did not differ significantly from the PR volume index and PR percentage derived from the MR velocity flow measurements (28 mL/m2 ± 18 and 36% ± 20; P = .21 and P = .45, respectively). Furthermore, good correlation was observed between PR measurements obtained with both techniques (PR volume index, r = 0.97, P < .001; PR percentage, r = 0.95, P < .001). PR was significantly higher in the patient group (n = 10) that underwent correction with the use of a patch for relief of pulmonary stenosis (PR percentage, 46% ± 8 with patch vs 9% ± 12 without patch; P < .001). Differences in exercise capacity between patients who underwent correction with and patients who underwent correction without use of a patch did not reach statistical significance (peak workload with patch, 163 W ± 38; without patch, 202 W ± 40; P = .09) (peak oxygen uptake with patch, 1,932 mL/min ± 435; without patch, 2,551 mL/min ± 738; P = .06) (peak oxygen uptake/body weight with patch, 35 mL · min-1 · kg-1 ± 5; without patch, 38 mL · min-1 · kg-1 ± 4; P = .32).

At rest, differences were observed in RV and LV function between patients and control subjects (Table 3). RV end-diastolic volume indexes of patients with corrected tetralogy of Fallot were higher than those of control subjects (Table 3), and they correlated significantly with PR volume indexes (r = 0.74, P = .002) (Fig 2). In eight patients, diastolic forward flow was observed in the pulmonary trunk, but there was no difference in exercise capacity or cardiac response to exercise between patients with and patients without diastolic forward flow.


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  		TABLE 3. Cardiac Response to Exercise

 


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  		Figure 2. Regression line of PR volume index (PRVI) and RV end-diastolic volume index (RV-EDVI). A significant correlation was observed between the amount of pulmonary regurgitation and end-diastolic volume of the RV (r = 0.74; P = .002).

 
Ejection fraction of the RV at rest was normal in 80% of patients with corrected tetralogy of Fallot. We found no correlation between PR or RV function and peak oxygen uptake per kilogram of body weight or maximal workload.

Cardiac Response to Supine Bicycle Exercise
In response to the submaximal exercise level at MR imaging, heart rate increased from 68 beats per minute ± 10 to 117 beats per minute ± 8 (P < .001) in patients and from 71 beats per minute ± 9 to 121 beats per minute ± 14 (P < .001) in control subjects. No difference in heart rate at the submaximal exercise level was observed between groups at MR imaging (Table 3).

In response to exercise, a decrease in PR volume index from 27 mL/m2 ± 17 to 23 mL/m2 ± 15 (P = .012) and a decrease in PR percentage from 35% ± 20 to 29% ± 17 (P = .001) were observed (Fig 3).



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  		Figure 3. Changes in PR volume index and PR percentage in response to supine physical exercise. Mean PR index and PR percentage significantly decreased from rest to exercise in patients with corrected tetralogy of Fallot.

 
RV response to exercise was different in the patient group than in the control group (Table 3). In the patient group, the RV end-diastolic volume index increased from 132 mL/m2 ± 36 to 137 mL/m2 ± 38 (P = .041) in response to exercise (Fig 4). RV end-systolic volume index and ejection fraction in the patient group did not significantly change in response to exercise, whereas RV stroke volume index increased from 69 mL/m2 ± 16 to 73 mL/m2 ± 15 (P = .045) (Fig 4). In only one patient, ejection fraction of the RV increased by more than 5% in response to exercise.



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  		Figure 4a. (a-d) Changes in RV volumes and function from rest to exercise in patients with corrected tetralogy of Fallot and control subjects as indexed to body surface area. The abnormal RV response in patients with corrected tetralogy of Fallot is evidenced by an increase in end-diastolic volume and no significant changes in end-systolic volume or ejection fraction. * = significant difference between values obtained at rest and during exercise.

 


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  		Figure 4b. (a-d) Changes in RV volumes and function from rest to exercise in patients with corrected tetralogy of Fallot and control subjects as indexed to body surface area. The abnormal RV response in patients with corrected tetralogy of Fallot is evidenced by an increase in end-diastolic volume and no significant changes in end-systolic volume or ejection fraction. * = significant difference between values obtained at rest and during exercise.

 


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  		Figure 4c. (a-d) Changes in RV volumes and function from rest to exercise in patients with corrected tetralogy of Fallot and control subjects as indexed to body surface area. The abnormal RV response in patients with corrected tetralogy of Fallot is evidenced by an increase in end-diastolic volume and no significant changes in end-systolic volume or ejection fraction. * = significant difference between values obtained at rest and during exercise.

 


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  		Figure 4d. (a-d) Changes in RV volumes and function from rest to exercise in patients with corrected tetralogy of Fallot and control subjects as indexed to body surface area. The abnormal RV response in patients with corrected tetralogy of Fallot is evidenced by an increase in end-diastolic volume and no significant changes in end-systolic volume or ejection fraction. * = significant difference between values obtained at rest and during exercise.

 
In contrast to findings in the patient group, RV end-diastolic volume index in the control group remained unchanged during exercise, and RV end-systolic volume index decreased from 32 mL/m2 ± 7 to 24 mL/m2 ± 6 (P < .001) (Fig 4). RV stroke volume index increased from 49 mL/m2 ± 6 to 56 mL/m2 ± 5 (P < .001), and ejection fraction increased from 61% ± 6 to 70% ± 6 (P < .001) (Fig 4). In all control subjects, RV ejection fraction increased by more than 5% in response to exercise.

LV response to exercise (Table 3) was not different between groups, as evidenced by no significant difference in the percentage change from rest to exercise in LV stroke volume (16% ± 13 in patients vs 14% ± 8 in control subjects; P = .579) and ejection fraction (16% ± 9 in patients vs 18% ± 7 in control subjects; P = .403). In both groups, LV end-systolic volume index decreased during exercise, whereas no change in end-diastolic volume index was observed. This resulted in an increase in LV stroke volume index and ejection fraction in both groups. In 12 (80%) patients, LV ejection fraction increased by more than 5% in response to exercise, whereas LV ejection fraction increased by more than 5% in all control subjects. We found no correlation between changes in PR, RV function, or LV function in response to exercise and peak oxygen uptake per kilogram of body weight or maximal workload.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Results of this study show the feasibility of using an optimized exercise protocol at MR imaging to evaluate PR and biventricular function in response to exercise in patients with tetralogy of Fallot that was corrected at a young age. The main observations in the patient group were the following: (a) PR decreased with supine physical exercise; (b) the RV response to exercise in patients was abnormal compared with response in control subjects, as demonstrated by increased end-diastolic volume, lack of decrease in end-systolic volume, and no change in ejection fraction; and (c) the LV reaction to supine exercise in patients was not different from that in control subjects.

Exercise Protocol at MR Imaging
MR imaging is an accurate and noninvasive technique for the evaluation of PR and biventricular function at rest (7). Pedersen et al (32) reported on the use of a dedicated exercise protocol to assess changes in blood flow in the abdominal aorta in response to exercise. During this protocol, measurements were obtained during short exercise breaks of 12 cardiac cycles (32). Recently, biventricular function was assessed in response to submaximal exercise in healthy volunteers by using a dedicated MR imaging exercise protocol in which measurements were obtained during exercise breaks of eight cardiac cycles (19). The results of that study (19) showed that evaluation of biventricular function with the same ultrafast turbo-field echo-planar MR sequence that was used in our study could be performed with low inter- and intraobserver variability, and the observed biventricular response to exercise fitted well with current concepts of cardiac physiology.

In patients with PR, the amount of regurgitant flow can be calculated by subtracting LV stroke volume from RV stroke volume (17). The assessment of biventricular function during exercise, therefore, allows simultaneous evaluation of PR during exercise.

PR during Exercise
In most studies on the evaluation of PR and exercise capacity in patients with corrected tetralogy of Fallot, PR has been assessed with the patient at rest by using semiquantitative methods (9,33,34). Kondo et al (12) evaluated the grade of PR at rest and during exercise by obtaining the ratio of LV and RV stroke volumes with first-pass radionuclide ventriculography. Absolute measurement of PR was not possible, however, because LV and RV stroke volumes were measured at different time points (12). Therefore, quantitative data obtained on PR during exercise is lacking so far. In the current study, we used a submaximal exercise protocol (19) at MR imaging to evaluate PR during exercise. From rest to exercise, we observed a decrease in PR. Several factors may have contributed to this decrease. Pressure in the RV and pulmonary circulation are important determinants of the severity of PR (34). Alterations in pressure in response to exercise may contribute to changes in PR during exercise. In healthy subjects, RV diastolic pressure decreases during exercise (35). In contrast, an increase in RV end-diastolic pressure was found in patients with corrected tetralogy of Fallot with PR (35–37). The abnormal responses of RV diastolic function and pressure to exercise are influenced by myocardial fibrosis and hypertrophy of the RV (35). Both factors can be present in patients with corrected tetralogy of Fallot (7,38,39). The decrease in PR in response to exercise as observed in the present study may, therefore, be a characteristic of altered diastolic function of the RV in response to exercise. This is in accordance with the hypothesis of Gatzoulis et al (25), which states that at rest, diastolic RV dysfunction may limit the amount of PR.

Changes in diastolic pressure in the pulmonary artery during exercise may affect PR. However, in the few studies in which investigators evaluated pulmonary hemodynamics after tetralogy of Fallot correction, no marked changes in pulmonary pressure were reported (40,41).

Finally, the increase in heart rate during exercise and the accompanying decrease in diastolic time result in a shorter time period in which regurgitation can occur. This time limitation may also lead to a decrease of PR during exercise.

Ventricular Response to Exercise
Although RV function in patients at rest was impaired in comparison to function in the control subjects, RV ejection fraction was within normal range in 80% of patients. RV ejection fraction response to exercise, however, was abnormal in 93% of patients. Furthermore, in the patient group, no changes in RV ejection fraction or RV end-systolic volume were observed during exercise, whereas an increase in end-diastolic volume was evident. The increase in RV end-diastolic volume accounted for the increase in RV stroke volume during exercise. The combination of an increase in end-diastolic volume index and a lack of decrease in end-systolic volume index in response to supine exercise is normally seen in older healthy subjects (42) and in patients with ischemic heart disease (43). In the healthy control subjects, RV stroke volume increased due to a decrease in end-systolic volume with no change in end-diastolic volume, which is in accordance with previous reports (44,45).

In patients with corrected tetralogy of Fallot, the abnormal response of RV ejection fraction to exercise that was observed in other studies (46,47) was mainly ascribed to the deleterious effects of chronic volume overload on RV function. In our patients, PR percentage at rest was 35%, and a significant correlation between the amount of PR and RV volumes was observed. Therefore, our results confirm that long-standing volume overload is related to RV dilatation at rest and is likely an important factor in causing RV dysfunction in response to physical supine exercise (46,47).

In eight patients, diastolic forward flow was observed in the pulmonary artery, indicating restrictive diastolic dysfunction of the RV (24–26). In children (mean age, 12 years; mean age at surgical correction, 1.5 years), restrictive RV physiology has been related to impaired exercise capacity (18,26). In adults (mean age, 29 years; mean age at surgical correction, 5.2 years), restrictive RV filling predicted superior exercise performance (25). In the current study, in which we evaluated patients aged approximately 18 years (mean age at surgical correction, 2.1 years), we observed no difference in exercise capacity or cardiac response to exercise between patients with and patients without diastolic forward flow in the pulmonary artery. The observations made in various groups may indicate an interaction between restrictive diastolic RV function and exercise capacity that is related to age or follow-up time.

The depressed LV function at rest in patients with corrected tetralogy of Fallot confirms earlier reports and is ascribed to the deleterious effect of chronic volume overload of the RV (6,7). The normal LV response to exercise observed in most patients with corrected tetralogy of Fallot, however, suggests that LV function is relatively well preserved in our patients (42).

Exercise Capacity
Oxygen uptake and workload levels at peak exercise were significantly lower in patients than in control subjects. Several investigators observed an association between PR and exercise impairment (9–11,26). We found no correlation between PR or RV function and peak oxygen uptake per kilogram of body weight or maximal workload, although patients whose correction involved the use a patch for relief of pulmonary stenosis tended to have higher PR and lower exercise capacity. Several factors may explain the absence of correlation between cardiac dysfunction and exercise impairment.

We found little evidence for the compromising influence of cardiac dysfunction on ventilatory function during exercise as suggested by Rowe et al (9). No differences in breathing reserve, peak ventilation, or breathing frequency were observed between groups. Furthermore, most patients had a normal breathing reserve, and none of the patients recorded dyspnea as the reason for stopping exercise. The patients in the study of Rowe et al (9), however, underwent correction at an older age. The better outcome in our patient group may reflect the beneficial effect of undergoing correction at a young age (48,49).

Differences regarding methods are apparent between our study and others. We used a quantitative approach to measure PR at rest and during exercise, whereas other investigators categorized patients as having no PR, mild PR, moderate PR, or severe PR on the basis of semiquantitative assessment of PR at rest (9–11,33, 34). Shifting patients from the mild to more severe PR groups and vice versa, which is easily conceivable with the use of semiquantitative methods, may alter statistical analyses (50). Furthermore, our exercise protocol has important differences from protocols in other studies. Our patients performed a graded maximal exercise test on a bicycle in the supine position, whereas others used a treadmill or had patients perform exercise while sitting upright on a bicycle (9–11,26). Body position clearly influences diastolic ventricular function (51). In the presence of an incompetent pulmonary valve, body position may affect PR and its effect on exercise performance.

Limitations
In patients with corrected tetralogy of Fallot, a higher breathing frequency in response to exercise has been reported, which may act as a respiratory pump to support pulmonary hemodynamics (52). Performing breath holding during exercise may potentially interfere with this additional hemodynamic support. We did not monitor breathing frequency during the MR imaging examination, but during the maximal exercise test we observed no difference in breathing frequency between groups. We therefore conclude that the performance of breath holding did not cause patient measurements to differ from those of the control subjects.

At rest, no patient had important atrioventricular or aortic valve regurgitation, and therefore, PR could be calculated by subtracting LV stroke volume from RV stroke volume. During exercise, neither atrioventricular nor aortic valve flow was evaluated. No data are available on the potential occurrence of exercise-induced atrioventricular or aortic valve regurgitation during exercise in patients with corrected tetralogy of Fallot. However, no exercise-induced mitral valve regurgitation occurred in response to supine bicycle exercise in patients without mitral valve regurgitation at rest (53). On the other hand, in the case of exercise-induced tricuspid valve regurgitation, our assessment of PR during exercise is overestimated, since part of the RV stroke volume will enter the right atrium.

Clinical Implications
Our results stress the deleterious effects of PR-induced chronic volume overload of the RV and raise concerns about RV function late after tetralogy of Fallot correction that was performed at an early age. Therrien et al (14) observed no improvement in RV function after pulmonary valve replacement in patients with corrected tetralogy of Fallot, and the authors state that pulmonary valve implantation should be considered before RV function deteriorates. In our study, RV ejection fraction at rest was normal in 80% of patients who had undergone surgical repair at a younger age than those in the study of Therrien et al (14). However, MR imaging revealed an abnormal RV response to exercise in 93% of patients, most likely as a result of long-standing volume overload. These findings underline the importance of either avoidance of PR at corrective surgery or the use of strategies for early restoration of pulmonary valve competence. Furthermore, exercise MR imaging may prove to be an important imaging tool in the timing of reintervention after tetralogy of Fallot correction by allowing detection of early RV dysfunction in patients with normal RV function at rest.


   ACKNOWLEDGMENTS
 
The technical assistance of Robert G. M. van Steijn of the Department of Pulmonology at Leiden University Medical Center is gratefully acknowledged.


   FOOTNOTES
 
2 Current address: Erasmus Medical Center-Sophia’s Children Hospital, Rotterdam, the Netherlands. Back

Abbreviations: LV = left ventricle, PR = pulmonary regurgitation, RV = right ventricle

Author contributions: Guarantors of integrity of entire study, W.A.H., E.E.v.d.W., A.d.R.; study concepts, A.A.W.R., W.A.H., P.K., H.J.L., A.d.R., E.E.v.d.W.; study design, all authors; literature research, A.A.W.R., W.A.H., P.K., J.G.v.d.A.; clinical studies, A.A.W.R., W.A.H., P.K., J.G.v.d.A.; data acquisition, A.A.W.R., P.K., W.A.H., J.G.v.d.A., H.J.L.; data analysis/interpretation, all authors; statistical analysis, A.A.W.R., W.A.H., P.K., H.J.L.; manuscript preparation, A.A.W.R., W.A.H., P.K., A.d.R.; manuscript definition of intellectual content, all authors; manuscript editing, A.A.W.R., W.A.H., P.K., J.G.v.d.A., H.J.L., E.E.v.d.W., A.d.R.; manuscript revision/review and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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