Discussion
We have demonstrated a positive association between O2 pulse slope to peak exercise and SV, in patients with a Fontan circulation. We have also confirmed the lack of association between peak O2 pulse and SV, as previously demonstrated by other authors.14 Our data suggest that O2 pulse slope, which incorporates O2 pulse kinetics across exercise, may be a better surrogate marker than absolute peak O2 pulse of maximal SV during exercise in Fontan patients.
SV and the a-vO2 difference
O2 pulse is determined by SV and oxygen extraction (a-vO2 difference). In untrained healthy subjects, SV increases during exercise but then plateaus at a submaximal load.20 The a-vO2 difference, however, increases as a linear function during exercise in healthy subjects, and is the main determinant of O2 pulse from mid-exercise.10 SV and a-vO2 difference responses across exercise in patients with a Fontan circulation appear to be more heterogeneous.
SV has been shown to increase throughout exercise in some Fontan patients but plateau or decrease in others at maximum exertion.14 21–24 This variable SV response may relate to differences in underlying patient characteristics but also to differences in the way SV is measured across different studies. Although submaximal and maximal HR is lower in Fontan patients than healthy controls,6 24 25 the slope of the response of HR against workload or VO2 appears to be higher or equivalent.6 24 The exercise chronotropic response of patients with a Fontan circulation may thus be adaptive to preload insufficiency in order to maintain ventricular filling and cardiac output. In keeping with these data, we did not find a difference in the O2 pulse slope up to AT between Fontan patients and controls.
In a small study of 10 Fontan subjects before and after a single dose of sildenafil, Van De Bruaene et al showed decreasing SV (measured by ExCMR) and increasing a-vO2 difference (measured from direct arterial and venous blood sampling) from rest to peak exercise.23 In a study of 15 children with a Fontan circulation, Strömvall Larsson and Eriksson showed increasing a-vO2 difference across exercise but with considerable variability in the difference at peak exercise (median 16.8, range 10.5–21.5 mL/100 mL).22 Rosenthal et al demonstrated higher a-vO2 difference in 43 children with a Fontan circulation compared with healthy controls at rest and across all stages of exercise.26
The impact of chronic cyanosis on a-vO2 has been poorly studied. It is possible that cyanosis, related to the either the presence of a fenestration or systemic venous collateral, results in a reduced ability to augment oxygen extraction at peak exercise or impaired microcirculatory function. We found no association between O2 pulse parameters and either the presence of a fenestration or resting or peak oxygen saturation. This is in keeping with a study by Loomba et al showing similar exercise arterial-venous saturation difference (utilising regional near infrared spectroscopy) in fenestrated versus non-fenestrated Fontan patients27 and a study by Strieder et al showing similar tissue oxygenation during exercise in cyanotic versus repaired acyanotic CHD.28 We speculate that a more heterogeneous a-vO2 difference during exercise in patients with a Fontan circulation may explain the poor association of peak O2 pulse with SV. However, this would need to be examined in a future study where exercise SV, O2 pulse and a-vO2 difference are directly measured.
Association between O2 pulse slope and clinical variables
In our exploratory study, we found no association between clinical variables and O2pulseslopePEAK or O2pulseslopeAT, apart from a weakly positive association with baseline FVC %predicted. There was no association with other spirometry parameters.
Fontan subjects have been shown to have abnormal spirometry, with an association between FVC and peak VO2.19 29 Its association with O2 pulse slope is beyond the scope of this study, however, may reflect a ventilation driven inability to augment pulmonary blood flow, and therefore, SV.
O2 pulse and long-term outcomes
Neither O2 pulse nor its change over serial testing have been shown to predict long-term adverse Fontan outcomes.30 We speculate that, in part, this relates to its poor correlation with SV in Fontan patients. It would be of interest to investigate the association between O2 pulse slope and its change and long-term Fontan outcomes.
Implications of study findings and study limitations
In a study of 411 Fontan subjects (age 12.4±3.2 years, 166 achieving a maximal exercise test) Paridon et al found, as expected, that per cent predicted peak O2 pulse was strongly associated with per cent predicted peak VO2 and moderately with per cent predicted VO2 at AT.3 Based on the strength of these associations, the authors inferred that SV limitation was solely responsible for the variation in aerobic performance. However, our data suggest caution in using peak O2 pulse as a surrogate marker for SV in Fontan patients. We speculate that this may relate to a greater variability in the a-vO2 difference at peak compared with submaximal exercise.
As this was a preliminary study, our study cohorts were small, and we did not have exCMR data available for cohort B. However, even based on our small cohort A, we were still able to demonstrate a moderately significant association between O2 pulse slope to peak exercise and peak SV.
Our exCMR protocol was performed using recumbent exercise, likely producing submaximal exercise testing; compared with our upright cycle ergometer CPET. The use of serial gas measurements and CMR-augmented CPET, including continuous oxygen saturation monitoring, would have allowed simultaneous assessment of gas exchange, and a-vO2 during exercise.
Our healthy controls were retrospectively obtained from subjects previously undergoing CPET, and therefore, we did not have a prospectively matched cohort. However, given the older age of the control subjects, we are more likely to have underestimated the significance of the difference between our Fontan and control cohorts.
Given our relatively small sample size and short-term follow-up, we were unable to examine whether O2 pulse slope predicted adverse long-term Fontan outcomes. In our exploratory analysis of cohort B, adjustments for multiple comparisons were not performed, increasing the risk of type I error. Further larger studies would be of interest to analyse the association between O2 pulse parameters and clinical variables.