Right Ventricular Diastolic Function 15 to 35 Years After Repair of Tetralogy of Fallot
Restrictive Physiology Predicts Superior Exercise Performance
Background We have shown previously that transient right ventricular restriction after tetralogy of Fallot repair prolongs postoperative course. This is a prospective study of right ventricular diastolic performance in late follow-up patients.
Methods and Results We studied biventricular function, using Doppler echocardiographic examination. Pulmonary arterial, tricuspid, and mitral valves and superior vena cava Doppler spectrals were obtained in 41 patients (mean age, 28.8 years), 15 to 35 years (mean, 23.6) after complete repair of tetralogy of Fallot. Patients were considered to have evidence of right ventricular restriction if antegrade diastolic flow was detected in the main pulmonary artery, coinciding with atrial systole (A wave), throughout the respiratory cycle. Exercise function was measured by graded treadmill testing with respiratory mass spectrometry. Three patients were excluded because of pulmonary outflow obstruction (Doppler gradient >40 mm Hg) or residual intracardiac shunts. Of the 38 patients, 37 were in sinus rhythm. Twenty (52.6%) had definite evidence of restriction with an A wave in the pulmonary artery, augmented during inspiration. In all 20 cases, there was superior vena caval flow reversal with atrial systole. Both inspiratory and expiratory transtricuspid E-wave deceleration time was significantly shorter in the restrictive group (P<.003 and P<.03, respectively). All patients had Doppler evidence of pulmonary regurgitation, but its duration was shorter in the restrictive group (P<.01) during inspiration. Cardiothoracic ratio was significantly lower in the restrictive group (P<.01), suggesting less severe pulmonary regurgitation. Both restrictive and nonrestrictive groups had reduced exercise MV̇o2 compared with healthy age- and sex-matched control subjects, but those with restrictive physiology had significantly better maximum oxygen uptake than the nonrestrictive group (P<.001).
Conclusions Isolated right ventricular restriction late after tetralogy of Fallot repair is common. Although it reflects abnormal hemodynamics, the A wave contributes to forward pulmonary arterial flow and shortens the duration of pulmonary regurgitation. Consequently, there is less cardiomegaly and improved exercise performance in those patients.
Biventricular repair of tetralogy of Fallot has been performed for almost four decades, with a favorable long-term outcome in most patients.1 2 In recent years, interest has centered around the effects of operation on right ventricular systolic function and exercise performance. As operative techniques and myocardial protection have improved, left ventricular function has been shown to be well preserved after early repair.3 Right ventricular diastolic function, particularly in the current era of even earlier correction with its invariably higher transannular patch rate, needs further evaluation. Although normal before,4 5 right ventricular volumes may increase and ejection fraction decrease after repair.6 7 8 We have shown previously that pulmonary regurgitation, which is now recognized as one of the most important factors in the late follow-up of these patients, is directly related to right ventricular dilation.9 Its association with reduced exercise capacity is now established,10 11 and there is increasing evidence to support its adverse role in the development of arrhythmias and possibly sudden death.12 There can be no doubt, therefore, about the emerging importance of right ventricular diastolic events for the long-term outcome of tetralogy of Fallot repair.
We have recently demonstrated transient abnormalities of right ventricular diastolic function in patients undergoing corrective surgery for tetralogy of Fallot, which prolong their postoperative recovery.13 Pulsed Doppler echocardiography demonstrated forward diastolic flow in the pulmonary artery coincident with atrial systole. Our report focuses on laminar antegrade pulmonary arterial flow in late diastole present throughout the respiratory cycle, which may be seen occasionally in normal children,14 although without documented pulmonary valve opening, and was seen in only 6 (all with right ventricular disease) of 750 adults undergoing echocardiography in another study.15 We proposed that this forward diastolic pulmonary arterial flow reflects reduced right ventricular diastolic compliance, suggesting that the right ventricle is unfillable and truly “restrictive” at end diastole, so acting as a passive conduit between right atrium and pulmonary artery during atrial systole.16
In this study of a self-selected cohort of adult survivors of early surgery, we have used the presence of antegrade diastolic pulmonary arterial flow as evidence of right ventricular restriction and examined its relation to other important indices of right ventricular diastolic function and overall functional performance measured using a formal exercise protocol.
We have performed a prospective study of 41 patients who underwent total repair of tetralogy of Fallot at the Westminster Hospital by a single surgeon between 1958 and 1979. Thus, follow-up ranges from 35 to a minimum of 15 years. Contact addresses were available for 80 patients who replied to a written questionnaire regarding their functional and social status in 1987. We were unable to contact 31 patients who were lost to follow-up. Six patients declined to participate. Two patients died, 1 from sudden death and the second from right heart failure. The 41 responders to our formal invitation constitute our study population. Their age at the time of the study was from 16 to 46 years (mean, 28.8 years), and their age at complete repair was from 9 months to 18 years (mean, 5.2 years). Surgery was performed under profound hypothermia. Right and left heart bypass was used, with the patient’s lungs being used as oxygenators until 1963 (8 patients) and traditional cardiopulmonary bypass thereafter. Access was via a combined right atriotomy and ventriculotomy although in seven cases the transatrial/transpulmonary approach was used. Further anthropometric details including previous surgery and operative techniques are shown in Table 1⇓.
This study took place at the Royal Brompton National Heart and Lung Hospital between August 1993 and March 1994.
All patients were studied echocardiographically using a 2.5- or 2.0-MHz transducer interfaced with a Hewlett-Packard Sonus 1500 ultrasound system. Transthoracic imaging was performed with the patient in the left lateral decubitus or supine position for the suprasternal views. Initially routine diagnostic imaging, including color flow mapping, and continuous-wave Doppler recordings were obtained. An M-mode recording of the left ventricular cavity in the parasternal long-axis view was recorded. Finally, pulsed Doppler recordings were made in each patient (see Table 2⇓): (1) pulmonary arterial systolic and diastolic Doppler characteristics (the pulsed Doppler sample was placed at the midpoint between the pulmonary valve leaflets and bifurcation), (2) superior vena caval Doppler profile (1 to 2 cm proximal to the right atrium), (3) transtricuspid valve characteristics (at the level of the tips of the valve leaflets), E- and A-wave velocity/integral, and E-wave deceleration time, and (4) transmitral valve characteristics (at the level of the valve leaflets), E- and A-wave velocity/integral, and E-wave deceleration time.
Measurements were made with simultaneous ECG, phonocardiogram, and respiratory motion recordings. Spectral recordings were made with minimal filtering on paper at a speed of 100 cm/s. Doppler recordings were analyzed according to the phase of the respiratory cycle, as previously described.15 Briefly, three consecutive inspiratory and three consecutive expiratory cardiac cycles (defined respectively as the first cardiac cycle after the onset of the inspiratory and expiratory deflection on the respirometer) were analyzed by planimetry and the results for each of the indices averaged.
Qualitative assessment of superior vena caval Doppler spectrals were made, with particular emphasis on the presence or absence of retrograde diastolic flow.
A detailed assessment of right ventricular inflow was performed using trans–tricuspid valve E- and A-wave peak velocities, duration, integral, and E-wave deceleration times. Systolic and diastolic pulmonary artery antegrade Doppler spectrals (peak velocity, duration, integral) were analyzed, as was the duration of pulmonary regurgitation. Restrictive physiology (group 1) was defined from the presence of laminar antegrade diastolic pulmonary arterial flow throughout the respiratory cycle (Fig 1⇓).13
Left ventricular shortening fraction was derived from the M-mode recordings in the usual way. Right and left ventricular long-axis length and atrioventricular ring diameter were measured from two-dimensional echocardiograms in the four-chamber view at end diastole. All patients had a 12-lead surface resting ECG and a chest radiograph in the posterior-anterior projection.17
Thirty-one patients agreed to perform treadmill exercise using a modified Bruce protocol. Thirty-one normal subjects were used as a control group. Control subjects were recruited from among hospital staff and were known not to have any previous history of cardiopulmonary disease. The control group was matched for age, body surface area, and predicted peak V̇o2.18 None of the patients or the control subjects were habitual exercisers or on any medication. Each subject undertook treadmill exercise using a Bruce protocol modified by the addition of a “stage 0,” that is, 3 minutes at 1 mph, with a 5% gradient. Patients breathed room air through a one-way valve connected to a respiratory mass spectrometer (Innovision). Ventilation (V̇e), carbon dioxide production (V̇co2), and oxygen consumption (V̇o2) were calculated on line every 10 seconds using an inert gas dilution technique.19 20 Once ventilation had become stable at rest for at least 2 minutes, patients were encouraged to exercise to exhaustion. Blood pressure was measured by sphygmomanometry. Peak blood pressure was obtained when the exercising patient indicated that he or she needed to stop. In some patients, a marked respiratory swing was noted. In these patients, the highest recorded blood pressure was taken. Heart rate was measured from the ECG. Respiratory rate was calculated as the average of the last five breaths from the capnograph. Patients and control subjects in whom the respiratory quotient at maximal exercise failed to exceed 1.0 were excluded because inadequate effort may have limited their performance.
Group data are expressed as mean±SD. Student’s t tests were used to compare normally distributed variables; otherwise, a Mann-Whitney U test was performed. Superior caval flow characteristics were compared using a standard χ2 test. Exercise data were analyzed across the three groups (restrictive, nonrestrictive, and control subjects) with ANOVA and where a significant difference was found were further investigated with Student’s t test adjusted for multiple comparisons (χ2 test). Regression analysis was performed using the method of least squares. The null hypothesis was rejected when P<.05.
Of the responders to the original questionnaire in 1987, 83.8% were in New York Heart Association functional class I, with 62.5% in full-time employment. Thirty-nine of the 41 responders to our formal invitation to participate in the current study were in functional class I (95.1%), with 75.6% in full-time employment. These differences were not statistically significant, suggesting that although the patients participating in our study were “self-selected,” there was no selection bias from the larger group from 1987. Two patients were excluded because of significant right ventricular outflow obstruction (Doppler gradient >40 mm Hg) and 1 because of an atrial septal defect. Anthropometric details for the 38 patients included in the study with details regarding previous palliation, operative techniques, and need for procedures after repair are shown in Table 1⇑. All except one patient were in sinus rhythm, and all of them had a right bundle branch block QRS pattern in their surface ECG.
Pulmonary Arterial Flow
There were 20 patients with restrictive physiology (group 1). In the remaining 18 patients (group 2), there was either no antegrade diastolic flow or transient flow restricted to the inspiratory phase of respiration. The A wave in the pulmonary artery, our marker of right ventricular restriction, accounted for 3.5% to 25% of the total forward (systolic and diastolic) pulmonary artery Doppler integral in group 1. There was a marked augmentation (30% to 58%) of the flow integral during inspiration. There was no significant difference in heart rate between the two groups at the time of study (mean, 68±10/min for restrictive patients and 75±12/min for nonrestrictive patients, P<.08). The duration of pulmonary regurgitation was significantly shortened in group 1 (300.2±65.4 versus 442.1±54.1 milliseconds, P<.01) during inspiration.
Transtricuspid E- and A-wave velocities, duration, and integrals were measured in 37 of 38 of the study group (Table 3⇓). The E-wave deceleration time was significantly shorter in group 1 in both inspiration (P<.003) and expiration (P<.03) (Fig 2⇓). Duration of E and A waves was shorter in expiration. The E/A velocity and integral ratios were similar in the two groups, however.
Superior Vena Cava Flow
Retrograde flow in the superior vena cava, coincident with atrial systole (Fig 3⇓), was present in all patients from the first group and in only 8 of 18 from group 2. Peak velocity of this flow (mean, 20 cm/s) was significantly higher in group 1 (χ2 test, P<.02). In addition, predominant antegrade flow in the superior vena cava occurred during early diastole in 16 of 20 patients from the restrictive group.
Left Ventricular Function
Left ventricular systolic performance was grossly normal in all with the left ventricular shortening fraction ranging from 29% to 45%. Transmitral E- and A-wave velocities, duration, E-wave deceleration, integrals, and E/A-wave ratios were measured, and there was no evidence of reduced left ventricular compliance.
Cardiothoracic ratio measured from posterior-anterior chest radiographs was significantly lower in group 1 (mean, 0.513±0.04 versus 0.555±0.04, P<.01), indicating overall smaller heart size. Biventricular long-axis length and atrioventricular ring diameter could be measured reliably in 32 and 27 patients, respectively. Absolute right ventricular long-axis length and tricuspid valve diameter were lower in group 1 (P<.003 and P<.004, respectively). This difference was more marked (Table 4⇓) when expressed as a ratio of right/left ventricular long-axis length (P<.001) and tricuspid/mitral valve diameters (P<.001), suggesting that in this group of patients, the degree of right ventricular dilation guides the overall heart size and is clearly less severe in the restrictive group. There was significant correlation between cardiothoracic ratio from the chest radiograph and the ratio of right/left ventricular length from the long-axis recordings (r=.45, P<.001).
There were no adverse effects from any of the exercise tests. All except two patients were able to exercise to a point where the respiratory exchange ratio (RER) (V̇co2/V̇o2) exceeded 1.0, indicating at least near maximal exercise.21 These two patients were excluded from the analysis of the exercise data. The control subjects were matched for age, sex, and body surface area. In the Fallot group as a whole, the average peak oxygen consumption achieved was 35.3±7.5 mL · kg−1 · min−1, representing 93.6±15.3% of the age-predicted maximum but significantly lower than control subjects (P<.01). In addition, exercise time was significantly longer in the control group (1029±22 versus 888±111 seconds, P<.001). Within the tetralogy of Fallot group, patients from group 1 achieved a significantly higher percentage of predicted peak V̇o2 when compared with group 2 (100.5±14.2 versus 82.6±10.1, P<.001). We chose to use percentage of predicted peak V̇o2 in order to correct any random variation in the age, body build, and sex distribution between the two groups of patients. Thus, patients from group 2 are slightly younger and bigger, so that the importance of their lower peak V̇o2 is the greater as a proportion of what they would be expected to achieve. Pulse and blood pressure responses to exercise were not different between the two groups (Table 5⇓). There was no significant difference also in symptoms at peak exercise between the two groups (6 of 17 short of breath in group 1 and 3 of 12 in group 2; other patients stopped by fatigue). Resting pulmonary function (FEV1=94.3±11.9% in group 1, 93.5±22.7% in group 2, and FVC=102.3±15.7%, 102.1±27.7%, respectively) was not different between the two groups.
No significant difference was found between cases in which the patient’s lungs were used as oxygenators as opposed to conventional cardiopulmonary bypass used after 1963. In addition, it was interesting to note that previous palliations or approach for repair were not significant factors in determining whether restrictive right ventricular physiology developed.
Most of the important problems encountered during the late follow-up of patients after repair of tetralogy of Fallot can be related to abnormal right ventricular physiology. Elevated right ventricular end diastolic/end systolic volume indices,9 exercise intolerance,11 and ventricular arrhythmia12 are all influenced by residual pulmonary incompetence. Relatively few data are available concerning other right ventricular diastolic events, however. Our study shows that restrictive right ventricular diastolic dysfunction is present in a significant number of patients late after repair of tetralogy of Fallot. Twenty of 38 patients (52.6%) had Doppler detectable antegrade diastolic flow in the pulmonary artery during atrial systole. This abnormal flow, present throughout the respiratory cycle, reflects decreased right ventricular compliance. The resistance to right ventricular filling exceeds the pulmonary vascular resistance, and as a result, some or all of the transtricuspid atrial systolic flow, demonstrable by Doppler, results in antegrade pulmonary arterial blood flow, not right ventricular filling. Thus, the stiff right ventricle has a limited end diastolic volume and acts as a conduit between right atrium and pulmonary artery. The simultaneous retrograde flow in the superior vena cava in all and rapid deceleration of the early rapid filling velocity, seen in the transtricuspid flow spectral, is consistent with a restrictive right ventricle. The normal E/A-wave ratios in the restrictive group highlight the poor utility of such measurements. As the transtricuspid A-wave flow does not reflect right ventricular filling, this traditionally used index of ventricular filling is inappropriate in these circumstances. Similar Doppler phenomena have been described previously in adults with restrictive myocardial processes involving the right ventricle.22 However, the finding of antegrade diastolic flow has not been consistently documented, presumably because of coincident biventricular restriction with resultant elevation of left atrial and pulmonary arterial diastolic pressures and obviation of the pressure gradient between the right atrium and pulmonary artery. Because of possible confounding influences, we excluded patients with residual intracardiac shunts, significant residual right ventricular outflow obstruction (>40 mm Hg), or any lesion likely to raise the pulmonary arterial diastolic pressure. We also were rigorous in our definition of restrictive physiology. Only patients with laminar antegrade diastolic pulmonary arterial flow throughout the respiratory cycle were included in group 1. There was a clear-cut respiratory variation in these patients, however, with more pronounced pulmonary arterial A-wave flow, shorter duration of pulmonary incompetence, and more rapid E-wave deceleration on inspiration, illustrating the need to consider the effects of respiration whenever right heart hemodynamics are examined.23 Although abnormal, the antegrade diastolic pulmonary arterial flow seen in these patients is important because it contributes to forward flow and shortens the duration of pulmonary regurgitation, in both ways making an important contribution to antegrade pulmonary arterial flow and hence to cardiac output.
There was significantly less cardiomegaly in the restrictive group, presumably reflecting the limited right ventricular end-diastolic volume in these patients.17 The degree of right ventricular dilation after repair of tetralogy of Fallot has been correlated with the amount of residual pulmonary incompetence by Carvalho et al11 and others.7 Whether this lower cardiothoracic ratio is a primary (as a result of intrinsic myocardial disease) or secondary phenomenon (as a result of limitation of pulmonary regurgitation caused by the restrictive physiology itself) or a combination of both is not clear. It is easy to conceptualize the situation whereby an intrinsic myocardial restrictive process (for example, fibrosis) leads to these abnormal filling characteristics, which in turn limits the amount of pulmonary incompetence. This would certainly explain the not-infrequent clinical finding of a normal cardiothoracic ratio and lack of progressive right ventricular dilation seen in some of these patients, even when a transannular patch has been placed.
Endomyocardial fibrosis has been demonstrated in patients after repair of tetralogy of Fallot24 and in animal models of tetralogy of Fallot.25 Our patients underwent correction at a mean age of 5.2 years. The additional adverse effects of less sophisticated methods of cardiopulmonary bypass, ventriculotomy, and inadequate myocardial protection all might be expected to influence the diastolic performance of the right ventricle. The exact relation of these factors to each other remains unknown, but it might be that some degree of right ventricular fibrosis is not disadvantageous for the patient with tetralogy of Fallot. Wessel and coworkers10 showed a significant negative correlation between cardiothoracic ratio and exercise performance in their patients studied after repair of tetralogy of Fallot. They speculated that this relation reflected the adverse effects of residual pulmonary incompetence. This was subsequently confirmed by direct measurement11 and Doppler estimates,26 but no previous study has examined the mechanism for differences in the degree of pulmonary incompetence in these patients. Most of our patients had preservation of the pulmonary valve and annulus, unlike patients operated on in the current era. We cannot speculate how this will affect future cohorts of patients because there are so many factors to be taken into account. Nonetheless, and irrespective of the mechanism, it is clear that the theoretical benefits of increased antegrade flow with reduced retrograde flow (and hence increased cardiac output) are manifest in terms of overall functional performance in our patients. Although most were in functional class I, those with restrictive right ventricular physiology significantly outperformed the group with nonrestrictive ventricles when formally measured by graded exercise testing.
Anything that diminishes the effect of atrial systole may be detrimental. Thus, maintenance of sinus rhythm is particularly important for patients with right ventricular restriction. Although our patients were studied at a mean of 23.6 years after repair, their sinus rhythm was preserved in all except one, who had intermittent junctional rhythm. Despite the limitation of this study, in which patients were assessed at a single point in time, one could reasonably speculate that their hemodynamics had existed for some time at no obvious expense of their effective atrial activity. The very nature of isolated right ventricular restriction may explain this. Unlike left ventricular restriction, the right atrium is able to decompress itself by emptying into the pulmonary artery via the right ventricle. Thus, there is little or no elevation on the mean atrial pressure and no obvious atrial dilation, making atrial dysrhythmias less likely.
Limitations of the Study
Our patient population is not representative of current surgical practice. Repair was performed at a mean age of 5.2 years, and only 1 out of 41 required a transannular patch, the rest having their pulmonary valve annulus preserved. They are therefore a highly selected group of survivors of early surgery. There are, however, increasing numbers of such patients entering adult life, and our data reflect this population of historical survivors and act as a cohort against which contemporary results can be compared. While indeed the current trend toward early primary repair may reduce the risk of endomyocardial fibrosis, our data suggest that it might in turn predispose to more significant impact of pulmonary regurgitation, with its deleterious long-term effects. Careful, repeated evaluation of long-term right ventricular diastolic performance will be needed in these younger patients.
Right ventricular restriction occurs in a significant proportion of patients late after complete repair of tetralogy of Fallot, protecting them from the detrimental effects of severe pulmonary regurgitation.
We would like to acknowledge the late Charles Drew for his pioneering work in the field of open heart surgery in the United Kingdom. We also would like to thank Dr D. Gibson for his help with the analysis of the data and M. Josen for providing echo lab support.
- Received September 26, 1994.
- Accepted October 18, 1994.
- Copyright © 1995 by American Heart Association
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