Author + information
- Received October 23, 2000
- Revision received February 12, 2001
- Accepted February 26, 2001
- Published online June 1, 2001.
- Hideo Ohuchi, MD∗,*,
- Kenji Yasuda, MD∗,
- Satoshi Hasegawa, MD∗,
- Aya Miyazaki, MD∗,
- Motoki Takamuro, MD∗,
- Osamu Yamada, MD∗,
- Yasuo Ono, MD∗,
- Hideki Uemura, MD†,
- Toshikatsu Yagihara, MD† and
- Shigeyuki Echigo, MD∗
- ↵*Reprint requests and correspondence: Dr. Hideo Ohuchi, Department of Pediatrics, National Cardiovascular Center, Fujishiro-dai, Suita, Osaka 565-8565, Japan
This study investigated the influences of ventricular morphology, hemodynamics and clinical findings on exercise capacity in patients after the Fontan operation.
Determinants of exercise capacity after the Fontan operation remain unclear.
Peak oxygen uptake (PV̇o2) was determined in 105 patients by exercise test and compared to hemodynamics and clinical findings. Patients were divided into three groups based on ventricular morphology: those with a right ventricle (group RV), a biventricle (group BV) and a left ventricle (group LV).
Ten patients with atrioventricular valve regurgitation (AVVR) or hypoxia exhibited a low PV̇o2. After excluding these patients, although PV̇o2did not correlate with hemodynamics, except ventricular ejection fraction (p < 0.02), it correlated with age at the Fontan operation and exercise test (p < 0.002). The PV̇o2was higher in group LV (63 ± 9%) than in groups RV (55 ± 9%) and BV (55 ± 12%) (p < 0.01), while an inverse correlation between PV̇o2and age at operation was demonstrated only in group RV (p < 0.05). Groups RV or BV and age at exercise test were associated with a lower PV̇o2, whereas group LV was an independent predictor of a higher PV̇o2(p < 0.01). During 4.2 years of follow-up, a decrease in peak heart rate was related to a decrease in PV̇o2(p < 0.05). The PV̇o2decreased in group RV (p < 0.01).
In addition to AVVR, hypoxia, and heart rate response, ventricular morphology is related to exercise capacity. Early Fontan operation may be beneficial in terms of exercise capacity, especially in the group RV patients.
An abnormal cardiorespiratory response to exercise characterizes post-Fontan operation patients (1–12). However, the determinants of aerobic exercise capacity remain unclear, and studies with a large number of patients are necessary. Although various modifications of the Fontan operation have been applied to complex congenital heart malformations (13,14), there are few studies of the influence of type of operation, ventricular morphology, hemodynamics and pulmonary function on aerobic exercise capacity long after the operation (5). We studied the morphologic, hemodynamic and clinical features of single-ventricle physiology, which influence exercise capacity. We hypothesize that a longer time following Fontan repair, right ventricle and two-ventricle as the systemic ventricle adversely influence exercise capacity.
Of the 230 patients who underwent the Fontan operation between October 1979 and October 1999 in our institute, 105 of 195 survivors who had performed exercise tests were included (aged 5 to 28 years; follow-up from 0.7 to 17.5 years). All patients had undergone cardiac catheterization one year after the operation to evaluate hemodynamics, and some of them underwent follow-up catheterizations 5 and/or 10 years following repair. They had performed an exercise test unless they had significant neurologic or orthopedic complications. At surgery, an atriopulmonary connection was created in 31 patients; total cavopulmonary connection by intra-atrial rerouting either with a polytetrafluorethylene tube was done in 39 patients or a heterologous pericardial baffle was done in 25 patients, thus anticipating growth of their own atrial wall to provide for an effective pathway in the future (13). Total cavopulmonary connection was achieved without cardiopulmonary bypass in another 10 patients (15). Fenestration was created at the time of the Fontan operation in three patients, in one of whom it closed spontaneously. Two patients who were converted from an atriopulmonary connection to a total cavopulmonary connection and one with ventricular tachycardia who had received a beta-blocker were excluded from the present study. The average number of previous surgical procedures in each group ranged from 1.0 to 2.4.
Cardiac catheterization, ventricular morphology and calculation of volume
In 97 patients, cardiac catheterization and cineventriculography were performed within one week of exercise testing. We measured central venous pressure, mean pulmonary artery pressure, pulmonary artery wedge pressure and end-diastolic pressure in the systemic ventricle (EDP). Oxygen consumption was estimated from the age, gender and heart rate data, and cardiac index (liter/min/m2) was measured using the Fick principle with the assumption that right and left pulmonary arterial saturations were equal in patients with a Glenn anastomosis. When the difference was >10% (n = 10), we referred to values of the supra and/or infra vena cava and used a reasonable value. Pulmonary (Rp) and systemic artery resistances (Rs) were also calculated.
Ventricular morphology was determined angiographically, and patients were divided into three groups, those with: 1) a dominant right ventricle with or without a rudimentary left ventricle (group RV, 40 patients); 2) a dominant left ventricle with or without a rudimentary right ventricle (group LV, 47 patients); and 3) presence of both right and left ventricles (group BV, 18 patients). Patients with two ventricles in whom the volume of the smaller ventricle was either >30% of the main ventricle or was >50% of its predicted normal value were included in group BV. In cases with inadequate imaging of the smaller ventricle, we referred to the echocardiographic findings, such as the location of the ventricular septum and to cineventriculograms performed prior to the Fontan operation. We were able to calculate biventricular volumes in 16 patients, whereas the other 2 patients were considered group RV on the basis of echocardiographic findings and previous cineventriculograms. Group BV patients underwent a Fontan operation because of small ventricular volumes or abnormalities of the atrioventricular valve.
Cineventriculography was performed in the anteroposterior and lateral projections with a film speed of 60 frames/s. The volumes of the morphologic right and left ventricles were calculated using Simpson’s rule or the area-length method. Adjustment for volume occupied by papillary muscles within the morphologic left ventricle was made as follows: measured volumes of the left ventricle >15 ml were adjusted to left ventricular volume = 0.96 × (calculated volume) − 3.3 (ml). Similarly, the right ventricular volumes were adjusted to right ventricular volume = 0.649 × (calculated volume). For standardization, end-diastolic ventricular volume index (EDVI) was divided by body surface area. Systemic ventricular ejection fraction (EF) was calculated as the ratio of stroke volume to end-diastolic volume (%). In group BV, when the image of both ventricles was clear, the volume of the larger ventricle was first determined and that of the other was measured at the end-systolic phase of the larger ventricle. The EDVI was calculated as the sum of both ventricles. End-systolic volume was calculated similarly, and EF was derived. When the image of both ventricles was unclear, we considered the two ventricles as a single ventricle and calculated EDVI and EF. Two of 21 patients were included in the latter group.
Patient characteristics, including previous operations or additional procedures at the time of the Fontan operation, are summarized in Table 1. In the present study, we included patients with pulmonary arteriovenous fistulae and fenestrated Fontans. The minimum arterial oxygen saturation was 80%, and significant hypoxia (<85%) was observed in three group RV patients.
Assessment of atrioventricular valve regurgitation
The atrioventricular valve regurgitation (AVVR) was assessed by color flow mapping, and was graded qualitatively as none-to-slight if the regurgitant jet crossed less than two-thirds of the systemic atrium from the atrioventricular valve orifice, and moderate-to-severe if it reached beyond two-thirds of the systemic atrium with a significantly wide jet. Plasty for AVVR was performed in 11 patients at the time of the Fontan procedure, and its magnitude decreased in 9 patients, with no improvement in 1. The atrioventricular valve was replaced in one patient. As a result, moderate-to-severe AVVR (significant AVVR) was documented in eight patients (five in group RV; three in group BV) and AVVR increased in one group RV patient during follow-up. One of them showed significant hypoxia. Finally, 10 of 105 patients had significant AVVR or hypoxia.
Pulmonary function tests
Ninety-one patients underwent pulmonary function tests a few days before or after each exercise testing. We measured vital capacity (ml); both the percent forced expiratory volume in 1 s (Spirosift, SP-600, Fukuda Denshi, Tokyo) and vital capacity were also calculated as the percentage of the body height-predicted normal value (VC) for our institute. Maximal voluntary ventilation was estimated by multiplying the forced expired volume in 1 s by 40 (16). Exercise breathing reserve was defined as 1 minus the ratio of minute ventilation at peak exercise to maximal voluntary ventilation and expressed as a percentage (17).
All patients exercised on a motor-driven, programmable treadmill (Q-5000 System, Quinton, Seattle, Washington). After a 3-min warm-up period (1.5 km/min and 0% grade), treadmill speed and grade were increased at 30-s intervals in increments calculated to increase oxygen uptake (V̇o2) by approximately 3.0 ml/kg/min per increment in normal subjects (18). All patients were exercised to the end of their tolerance.
A 12-lead electrocardiogram was recorded at rest and throughout exercise and was used to determine heart rate. Systolic blood pressure was measured every 2 min during exercise testing. Because it is difficult to measure blood pressure with a mercury sphygmomanometer during dynamic exercise, especially in younger patients, we measured systolic blood pressure by palpation. Ventilation and pulmonary gas exchange were measured by a computerized breath-by-breath method. Subjects breathed through a tight-fitting mask. A hot wire anemometer (Riko AS500, Minato Medical Science, Osaka, Japan) measured inspired and expired flow continuously. The partial pressures of o2and co2were measured continuously at the mouth with a mass spectrometer (MG-300, Perkin-Elmer, St. Louis, Missouri). From these source data the minute ventilation (liter/min), V̇o2(ml/min), co2production (ml/min) and the respiratory gas exchange ratio, and the o2and co2ventilatory equivalents (V̇E/V̇co2) were computed in real time. Peak V̇o2as well as V̇E/V̇co2at peak exercise were also expressed in terms of % of predicted normal values (PV̇o2). The normal data were obtained in a cohort of 65 male and 60 female patients aged 5 to 24 years (19). All patients were free of pulmonary or cardiac disease.
Determination of individual daily activity
In 75 patients, the time required for them to go to and from school on foot or by bicycle and time spent in physically active play and/or habitual exercise training during a one-week period was determined by questionnaire. Total time divided by seven was considered as an individual’s daily activity per day (h).
Repeated cardiac catheterization, pulmonary function and exercise testing
Follow-up evaluations were repeated a mean of 4.3 years (2.5 to 7.2 years) later in 32 patients (group RV = 16, group LV = 9, group BV = 7).
Differences in cardiopulmonary function were evaluated using one-way analysis of variance with the Scheffe post hoc test. Differences in cardiorespiratory variables between first and second cardiac catheterization, exercise and pulmonary function tests were evaluated by paired ttest. Univariate and stepwise multivariate linear regression analysis was used to detect independent predictors of PV̇o2. Simple regression analysis was used to determine correlations between continuous parameters obtained (StatView-J4.02, Abacus Concepts, Berkeley, California). Data are expressed as the mean ± SD. A p value of <0.05 was considered statistically significant.
After excluding 10 patients with AVVR and/or hypoxia, there was no difference in pulmonary function among the three groups (Table 2). Although no obstructive ventilatory impairment was observed, all groups showed restrictive change. The VC was inversely correlated with the number of surgical procedures (p < 0.001). During follow-up, VC decreased significantly (p < 0.01) (Table 3).
Hemodynamics and ventricular performance
After excluding 10 patients with AVVR and/or hypoxia, no difference in hemodynamics was found among the three groups, except for a lower EF in groups RV and BV than in group LV (Table 2).
In 32 patients studied serially, pulmonary artery wedge pressure, EDP and Rs all increased (p < 0.05 to 0.005), whereas EF decreased (p < 0.02) (Table 3). When the three groups were analyzed separately, pulmonary artery wedge pressure, EDP and Rs increased in group RV (p < 0.05 to 0.01). Cardiac index decreased (p < 0.05) and EDP tended to increase (p < 0.1) in group LV. No significant change in EF was demonstrated in groups RV and BV, but EF in group LV decreased significantly (by 9%) (p < 0.05).
Cardiorespiratory responses during exercise
Gas exchange ratio at peak exercise was >1.10 in all groups; therefore, maximal exercise was achieved in each group (Table 4).
No difference in heart rate at rest nor at peak exercise was observed, but peak heart rate correlated with PV̇o2(r = 0.23, p < 0.05). In the serial study, no significant change in peak heart rate was noted.
Systolic blood pressure
No significant differences in systolic blood pressure among the three groups were noted, nor did it change in the serial study. Although no significant pressure gradient was documented at cardiac catheterization, systolic blood pressure at rest and during the warm-up walk was significantly higher in seven patients who had undergone a repair of interruption or coarctation of the aorta when compared to patients without such history (p < 0.05).
After excluding 10 patients with AVVR or hypoxia, PV̇o2was 59 ± 10%. Although there was no difference in V̇o2at the anaerobic threshold, PV̇o2was higher in group LV (63 ± 9%, 27 ± 4 ml/kg/min) than in groups RV (55 ± 10%, 25 ± 4 ml/kg/min) and BV (55 ± 12%, 25 ± 6 ml/kg/min) (p < 0.05 to 0.01) (Fig. 1). In group BV, small-to-main ventricular volume ratio correlated inversely with PV̇o2(r = −0.72, p < 0.003) (Fig. 2).
The PV̇o2decreased in the 32 patients studied serially (p < 0.005). When comparing the three groups, only group RV showed a significant decrease in PV̇o2, by 13% (p < 0.001). Decrease in peak heart rate was related to that in PV̇o2(r = 0.41, p < 0.02) (Fig. 3).
The PV̇o2was significantly lower in the 10 patients with AVVR or hypoxia than in the other 95 patients (47 ± 15% vs. 59 ± 10%, p < 0.002; 22 ± 7 ml/kg/min vs. 26 ± 5 ml/kg/min, p < 0.05).
Ventilatory efficiency and its reserve
Because there was no difference in peak V̇E/V̇co2or ratio of peak minute ventilation to maximal voluntary ventilation, all groups had a similar ventilatory efficiency and ventilatory reserve at peak exercise.
Peak V̇E/V̇co2tended to increase during follow-up (p < 0.07), suggesting a progressive reduction of ventilatory impairment at peak exercise.
Pulmonary function, hemodynamics, and aerobic exercise capacity
Forced expired volume in 1 s (%) correlated inversely with PV̇o2, but its correlation was low (r = 0.24, p < 0.05). Pulmonary function did not correlate with peak V̇E/V̇co2. In the serial observations, change in pulmonary function had no effect on PV̇o2.
In 105 patients, PV̇o2did not correlate with central venous pressure, mean pulmonary artery pressure, or EDP. Significant linear and second-degree curve relationships existed between all indices, except Rp, and PV̇o2. Adjusted correlation coefficients were higher in curve relationships than in linear analyses. According to the analyses of curve regression, the maximum pulmonary artery wedge pressure, EDVI, EF, cardiac index and Rs were 6 (mm Hg), 72 (ml/m2), 62 (%), 3.3 (liter/min/m2), and 27 U·m2, respectively. However, when the 10 patients with AVVR and hypoxia were excluded, no hemodynamic indices correlated with PV̇o2, except EF (r = 0.26, p < 0.02).
In the serial study, although change in hemodynamics was not related to PV̇o2, the PV̇o2decreased only in group RV, by 13% (p < 0.001), and its decrease was greater than in the other two groups (both 4%) (p < 0.1).
Clinical findings and aerobic exercise capacity
After excluding 10 patients with AVVR and/or hypoxia, age at the time of Fontan operation inversely correlated with PV̇o2(r = −0.33, p < 0.002). With group analysis, this relationship was observed in group RV (r = −0.37, p < 0.05, Fig. 4). Previous pulmonary artery banding, Glenn anastomosis, or additional aortopulmonary anastomosis did not affect PV̇o2.
The PV̇o2was lower in the 33 patients with isomerism than in the 72 patients without isomerism (p < 0.05). However, there was no difference in PV̇o2when the 10 patients with significant AVVR and/or hypoxia were excluded.
Although anticoagulant or antiarrhythmic agents did not influence PV̇o2, it was significantly lower in the 49 patients with diuretics than in the 46 without (56 ± 10% vs. 62 ± 10%, p < 0.01).
Daily activity and age at examination
When we excluded the 10 patients with AVVR and/or hypoxia, PV̇o2correlated with both age at exercise test (r = −0.33, p < 0.002) and daily activity (r = 0.43, p = 0.0003).
Determinants of PV̇o2
Stepwise multivariate linear regression analysis using seven parameters that had a significant influence on PV̇o2(ventricular morphology, daily activity, diuretics, age at Fontan operation, age at exercise test, forced expired volume in 1 s, EF) showed that ventricular morphology and daily activity were associated with PV̇o2. After excluding daily activity, because it might be an alternative parameter of exercise capacity, ventricular morphology (group RV or BV) and age at exercise test were associated with PV̇o2, and ventricular morphology was an independent predicter of lower PV̇o2(p < 0.01).
In addition to the significance of AVVR and hypoxia, our study demonstrates that 1) systemic ventricular morphology significantly impacts on PV̇o2and 2) age at the time of Fontan operation influences aerobic exercise capacity, which was decreased significantly, especially in patients with a morphologic right ventricular systemic ventricle.
Ventricular morphology and aerobic exercise capacity
Patients with congenital heart disease with a left ventricle as their systemic ventricle have better aerobic capacity than do those with a right ventricle as the systemic ventricle (20). Low left ventricular EF is not related to poor exercise capacity in adult patients with chronic heart failure (21); however, group LV patients with a relatively high EF had the highest PV̇o2in our study. Extremely low EF is related to poor exercise performance (4)and this is supported by our results. The contribution of ventricular contractility to increased stroke volume is greater during moderate to severe exercise than during mild exercise (22), and the contractility reserve of the left ventricle may be greater than the right ventricle acting systemically (20).
In addition to the histologic and geometric characteristics of the right ventricle, Sano et al. (23)demonstrated poor adaptation of the right ventricle (less hypertrophy compared to the left ventricle) to systemic work. This may result in both afterload mismatch during exercise and a limited increase in cardiac output, especially during moderate to severe exercise. Impaired diastolic function has been demonstrated in Fontan patients (24,25), and the thinner-walled right ventricle may produce a smaller suction effect during early diastole than the thicker-walled left ventricle (26). Consequently, because diastolic function is also important to exercise capacity (27), a right ventricle as a systemic ventricle is a disadvantage for such patients.
In group BV, possible incoordinated contraction of the two ventricles at rest (28)may also occur during exercise, limiting any increase in cardiac output. Inverse correlation between the ratio of small-to-main ventricular volume and PV̇o2suggests that difficulty in coordinating contraction to produce effective cardiac output is present in two-ventricle Fontan patients. Moreover, significant pressure gradients exist even in normal ventricles during the cardiac cycle (26); inordinate pressure gradients in such eccentric-shaped ventricles during not only systole but also diastole may be more significant and their magnitude may increase during exercise. In addition, probable asynchronous electric conduction in such ventricles might be another mechanism causing incoordinate contraction and relaxation. Progressive impaired ventricular relaxation (29)may be, in part, responsible for the decrease in aerobic exercise capacity long after the Fontan operation.
Age at the Fontan operation and aerobic exercise capacity
Long-standing hypoxia and chronic volume overload before the Fontan operation are believed to cause progressive ventricular fibrosis (30,31), which must result in both systolic and diastolic dysfunction (24). The fact that age at definitive repair influences exercise capacity is apparent in patients with other cyanotic congenital heart disease (32). These findings suggest that earlier elimination of hypoxia and volume overload is advantageous for subsequent better exercise performance in Fontan patients (12). In the present study, only group RV patients had a significant decrease in PV̇o2, with an inverse relationship between age at Fontan operation and PV̇o2. Possibly the right ventricle as a systemic ventricle is more vulnerable to hypoxia and chronic volume overload than is the left ventricle. Except for inadequate ventricular hypertrophy (23), causing greater vulnerability to prolonged hypoxia or volume load in the right ventricle than in the left ventricle, precise mechanisms remain unclear. Left ventricular contractile function recovers well within one year after left-sided valvular surgery in adult patients with chronic mitral regurgitation (33). However, failure to improve in right ventricular function due to chronic pulmonary regurgitation after pulmonary valve replacement in patients with tetralogy of Fallot may be another proof of vulnerability of the right ventricle (34,35). In addition, the large percentage of isomerism hearts in group RV than in group LV, usually with complex cardiac lesions (36), may contribute to such vulnerability.
Type of Fontan procedure and aerobic exercise capacity
Our study failed to show any relationships between type of Fontan procedure and PV̇o2. Inclusion of a hypoplastic right ventricle between the right atrium and pulmonary artery or a direct atriopulmonary anastomosis may have some adverse effects, but such patients do not have a lower aerobic exercise capacity. This is probably due to increased systemic venous return and the contribution of working muscle contractions, which overcome the small hemodynamic differences caused by Fontan variants. Consequently, daily activity rather than type of procedure has a greater impact on PV̇o2because it may be related to the bulk of working muscles.
Cardiopulmonary function, heart rate response and aerobic exercise capacity
When taking unique adaptations to exercise into consideration (8), decrease in VC on follow-up, which might be explained by deconditioning of the respiratory muscles, may influence aerobic exercise capacity. Higher adjusted correlation coefficients (r) of curve regression analyses between PV̇o2and hemodynamic indices may indicate the existence of optimal hemodynamics for PV̇o2.
The major determinant of the limited increase in cardiac output seems to be an impaired increase in stroke volume (1). However, because a decrease in peak heart rate is significantly related to the reduction of PV̇o2during follow-up, chronotropic incompetence is, to some extent, a contributing determinant of aerobic exercise capacity.
Daily activity and aerobic exercise capacity
Favorable effects of exercise training on aerobic exercise capacity have been reported in Fontan patients (37). The inverse correlation between age at examination and daily activity suggests that deconditioning occurs in adolescence to early adulthood long after the Fontan operation.
The present study is not prospective. The Fontan procedure continues to evolve; during the 1980s the main procedure in our institute was an atriopulmonary connection, whereas total cavopulmonary connection predominated in the 1990s. Moreover, the Fontan operation is being applied to more complicated patients than ever before. Thus, it may be difficult to compare one patient to another in the same way. Unfortunately, a randomized study is difficult for both ethical and practical reasons. Another study limitation is that accurate measurement of biventricular volumes and calculation of EF are difficult in some group BV patients. It is difficult to obtain clear images of the two ventricles in one ventriculogram, and if two injections are performed, it may also be difficult to calculate EF because of incoordinated contraction of the two ventricles (27). Moreover, because of lack of a mixing chamber and/or relatively high percentage of arterial and venous collaterals from systemic to peripheral pulmonary arteries or systemic veins, measuring accurate flow (cardiac output) is clinically difficult.
A final limitation of the study is the influence of medication on aerobic exercise capacity. In our study, patients who had taken diuretics may be symptomatic compared to those who did not. However, because the criteria for treatment with diuretics was unclear, we are not able to evaluate their influence on PV̇o2precisely. Because there were no differences in ages at the time of Fontan operation and at exercise test, body size, daily activity, follow-up period or percentage of medications among the three study groups, we believe that ventricular morphology has an impact on aerobic exercise capacity long after the Fontan operation.
We thank Drs. Peter M. Olley, Professor of Pediatrics, University of Alberta, and Setsuko Olley for assistance in preparing the manuscript.
- atrioventricular valve regurgitation
- end-diastolic pressure of the systemic ventricle
- end-diastolic ventricular volume index
- systemic ventricular ejection fraction
- predicted peak oxygen uptake
- pulmonary artery resistance
- systemic artery resistance
- predicted vital capacity
- ventilatory equivalent for carbon dioxide production
- oxygen uptake
- Received October 23, 2000.
- Revision received February 12, 2001.
- Accepted February 26, 2001.
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