This study is the first randomized, double-blind, placebo controlled, crossover trial to evaluate the impact of sildenafil on measures of exercise performance in children and young adults with single ventricle heart disease. The crossover design allowed for each subject to serve as his/her own internal control, thereby reducing the possibility of confounding given the heterogeneity of the cohort’s native anatomy. The pre-placebo mean VO2
max of 30.5 ml/kg/min demonstrates that the cohort was relatively healthy in comparison to reported measures of exercise performance for the Fontan population9
. In this study there was no difference in VO2
max, the primary outcome measure, following sildenafil administration as compared to placebo. However, there was an improvement in ventilatory efficiency during peak and sub-maximal exercise, and there was a suggestion of improved oxygen consumption during sub-maximal exercise. In two subgroups (those with single left ventricular or mixed ventricular morphology (n
= 13) and those with BNP levels ≥ 100 pg/ml (n
= 12)), the improvement in oxygen consumption during sub-maximal exercise was statistically significant.
The benefit of sildenafil in other populations is well documented. Exercise capacity, as measured by the six-minute walk, has been shown to improve in children and adults with pulmonary hypertension following treatment with sildenafil14
. In the adult heart failure population there is a suggestion of a benefit from treatment with sildenafil and there is emerging data to suggest that PDE5 expression is part of the maladaptive myocardial response to injury22–24
. However, in the population with single ventricle congenital heart disease, data is scarce regarding the potential benefit of sildenafil or of any other PDE5 inhibitor although, given the underlying physiology of this circulation, it makes intuitive sense that a therapy targeted at pulmonary vascular resistance and the maladaptive ventricular response to stress would be useful.
Following Fontan completion, the pulmonary and systemic circulations are effectively separated save for the potential presence of a fenestration. However, unlike in normal physiology, there is no pre-pulmonary ventricle to help deliver blood through the lungs and back to the heart. As a result, the ability to increase cardiac output in the setting of increasing metabolic demand is highly dependent on both low PVR and low ventricular filling pressure; the two components of pulmonary afterload. In order to increase flow across the pulmonary vascular bed during exercise, pulmonary afterload must drop and central venous pressure, the driving force of flow in the absence of a pre-pulmonary ventricle, must increase. In a two-ventricle circulation pulmonary vascular resistance decreases to 40–50% of the baseline value with exercise25
, and an increase in right-heart pressure is key to reaching the increase in cardiac output of four fold or more at peak exercise. In this setting, right heart systolic pressure might approach 50 mmHg or greater26
. In the Fontan physiology, central venous pressure cannot reach these values. Therefore, a very low PVR during exercise is essential to achieve any substantial increase in cardiac output.
We found no significant effect of sildenafil on cardiopulmonary measures at rest. However, in post-Fontan physiology, resting cardiac output is sufficient to meet metabolic demands. A medication that impacts pulmonary afterload is therefore not likely to have a noticeable impact on resting measures except, perhaps, in the setting of a significant right-to-left shunt. In this scenario, a change in PVR might affect the shunt fraction resulting in an increased proportion of venous return traversing the lungs. This could be measured by an increase in the systemic oxygen saturation. In our population there was a suggestion of increased oxygen saturation at rest following sildenafil; a finding which has been noted previously27
, though this did not reach statistical significance. Even in the subgroup with echocardiographic evidence of patent fenestrations, the resting oxygen saturation did not increase significantly. However, it should be noted that the baseline oxygen saturation of 90.2% for this group suggests that patency by echocardiography is not the same as a physiologically important shunt.
We found no improvement in VO2
max after a six-week course of sildenafil; a surprising finding given the suggestion of a difference during submaximal exercise. It is not clear from a conceptual standpoint why sildenafil would improve moderate levels of activity but not peak activity. There may be a limitation inherent in Fontan physiology such that a reduction in pulmonary afterload alone is not sufficient to increase cardiac output, or it may simply be that sildenafil is of no benefit at peak levels of exercise. Alternatively, we know from a recent large cross sectional study that maximal VO2
, an effort dependent measure of exercise performance, is less reliable than effort independent submaximal indices9
. Measurements of VO2
max may be impacted by subject effort and are therefore inherently less reliable. Although maximal exercise capacity was unchanged in our study, both respiratory rate and minute ventilation were improved. This suggests that while sildenafil does not improve maximal oxygen consumption, its most significant effect is to increase ventilatory efficiency (as a smaller minute ventilation is required for carbon dioxide removal) and to improve ventilation – perfusion matching.
The suggestion of improvement in oxygen consumption at the anaerobic threshold, and the statistically significant improvement in two subgroups (those with single left ventricular or mixed ventricular morphology (13/28) and those with BNP ≥ 100 pg/ml (12/28)) are important findings of this study. The finding of statistical significance in the subgroup with BNP ≥ 100 pg/ml suggests that the impact of sildenafil might be more profound on those with ventricular distention and mild heart failure while the finding of statistical significance in the group with either left or mixed ventricular morphology suggests that there may be a ventricle-specific effect. Similar to the findings at peak exercise, ventilatory efficiency during sub-maximal exercise was significantly improved following sildenafil, again consistent with an improvement in ventilation – perfusion matching. Alternatively, the improved ventilatory efficiency may have resulted from sildenafil-induced bronchodilation which, by reducing air-trapping during exercise, engendered the observed increase in tidal volume and a presumed decrease in the dead space/tidal volume ratio. The available baseline FVC and FEV1 data did not, however, detect evidence of sildenafil induced bronchodilation.
This study demonstrates that sildenafil improved ventilatory efficiency and exercise performance at the anaerobic threshold but did not alter VO2
max. While the overall changes in this proof of concept study were small and were not associated with an increase in work rate, these changes would be important if they translate into an attenuated slope in the decline in exercise capacity typically seen through the adolescent years in children with this physiology11
. Although this study did not evaluate long term efficacy, if exercise capacity can be improved or maintained, this might result in a longer period of general wellness and an increase in the duration of transplant free survival after the Fontan.
The challenge of improving physiology following the Fontan operation is daunting. There are limited trials evaluating medical therapies that have not demonstrated a significant benefit28
. Two recent case reports of sildenafil describe improvements in protein losing enteropathy and plastic bronchitis18, 19
, complications typically associated with failing Fontan physiology. One report demonstrated an improvement in VO2
max following a single does of sildenafil29
and a second demonstrated a selective benefit of bosentan on six-minute walk performance30
. This is the first randomized clinical trial to suggest an improvement over time in measures of exercise performance following a medical intervention in children with single ventricle physiology late after the Fontan operation.