Although the long-term survival is favorable, patients with repaired tetralogy of Fallot (rTOF) have impaired exercise capacity as measured by diminished percent-predicted maximum oxygen consumption (%mVO₂) even before reaching adulthood, and exercise capacity declines over time [1–3]. Lower %m VO₂ is associated with worse health status and quality of life, and is a predictor of mortality in this population [4–6]. Measures of exercise performance on cardiopulmonary exercise test (CPET) can be variable within each patient and the determinants of exercise performance in rTOF have not been completely elucidated.

The variability in exercise performance in rTOF and incomplete understanding of its determinants are likely in part due to the many contributing factors to exercise performance, including ventricular function, pulmonary insufficiency, pulmonary function, and chronotropic competence [7–12]. Habitual exercise has been associated with better exercise capacity independently of ventricular function [7]. Diminished pulmonary function, indicating restrictive lung physiology, is associated with diminished exercise capacity in patients with single ventricles, and in adults with congenital heart disease, and has been recently demonstrated to be associated with lower exercise capacity in youth with TOF as well [8–10]. We have previously shown that greater HRR and a greater reduction in pulmonary insufficiency at peak exercise are associated with superior exercise capacity, but we did not find an association of pulmonary insufficiency severity and RV systolic function at rest with exercise parameters [11]. Additionally, while we found RV contractile reserve to be impaired in this population, with a decline in RV function at peak exercise, this change in ventricular function itself was not associated with exercise performance. Our prior study prospectively evaluated a smaller cohort of patients with rTOF (n = 32) [12]. The present study sought to validate and augment our prior findings, by evaluating whether HRR is significantly associated with exercise performance in a larger cohort of patients operated for TOF. We also sought to identify additional contributing factors associated with exercise performance in this population, including pulmonary function measured as FVC. Lastly, we aimed to identify factors associated with HRR since chronotropic health might be modifiable in rTOF.

In this study, we retrospectively analyzed factors associated with mVO₂% and HRR in a large cohort of patients with TOF that underwent CPET, CMR and habitual exercise survey as part of a research study. Our prior prospective study of TOF undergoing exercise testing showed greater HRR was associated with superior exercise capacity and therefore in this study we sought to validate and augment our prior findings in a large well phenotyped cohort. Our main findings were: 1) FVC was independently associated with %mVO₂, and 2) FVC, net forward flow in the main pulmonary artery, and the ability to reach maximum effort were independently associated with HRR.

Chronotropic incompetence with depressed maximal heart rate during exercise has been shown in patients with congenital heart disease after surgical repair including those with rTOF [26–29]. Importantly, chronotropic incompetence is a predictor of morbidity and mortality in adults with rTOF [30–32]. In normal hearts, stroke volume increases to certain degree during exercise and further increase in cardiac output (defined as stroke volume X heart rate) is accomplished by augmentation of the heart rate. Therefore, an adequate chronotropic response to exercise is necessary to achieve a normal maximal oxygen consumption. In patients with CHD, increases in stroke volume maybe impaired due to myocardial dysfunction and/or valvular abnormalities, therefore if these patients also have inadequate chronotropic response, they can have significantly impaired cardiac output during exercise [18]. We found that chronotropic response as measured by HRR was independently associated with exercise performance, after accounting for RV ejection fraction and degree of pulmonary insufficiency, however, this association did not persist when we restricted the analysis to the group of patients that achieved a maximal effort on CPET, likely because this group of patients has better chronotropic response. We have previously demonstrated a relationship between HRR and aerobic capacity in a smaller group of rTOF undergoing stress echocardiography [17,18]. In particular, we previously reported that HRR was associated with better exercise performance as measured by %mVO₂ [18]. Other studies have also shown that chronotropic impairment is a significant contributor to aerobic capacity in rTOF [11,12,29,33,34]. Similarly to our finding of no association between HRR and %mVO₂ in those that achieve a maximal exercise test, a study by Mulla and colleagues demonstrated no correlation between chronotropic impairment and exercise performance in a small groups of patients with rTOF after transannular patch repair [27]. Thus, one’s effort during exercise testing is important and needs to be taken into account. After we analyzed the effect of chronotropic response on %mVO₂, we pursued more analyses to investigate mechanisms underlying impaired chronotropic response in the same rTOF group. Proposed causes of chronotropic incompetence after repair of CHD include sinus node dysfunction, abnormal autonomic function, neurohormonal activation and cardiac arrhythmias [28,31,32,35,36]. Patients with documented cardiac arrhythmia or pacemaker were not included in our analysis. We were unable to assess autonomic function or neurohormonal activation in our study cohort. However, there was no evidence of arrhythmia or sinus node dysfunction as only seven patients (4.7%) had a baseline heart rate less than 60 bpm with a normal peak exercise heart rate.

In addition to the primary findings, we also found that FVC was directly associated with mVO₂% and HRR independently of RV ejection fraction and pulmonary regurgitation. Prior studies have shown that patients with rTOF have abnormally low FVC, consistent with restrictive lung physiology [27,29,37,38]. There are multiple possible underlying factors for impaired pulmonary function at rest and during exercise in rTOF such as chest wall or rib cage abnormalities after sternotomies and thoracotomies, abnormal development and growth of the lung and pulmonary vasculature, as well as residual hemodynamic issues related to underlying CHD [30]. Patients with TOF have abnormalities in the pulmonary vasculature even before birth and into adulthood, with evidence of altered alveolar development [39,40]. Furthermore, lung growth in rTOF may not accompany somatic growth as seen in healthy children, given evidence of lower resting spirometry measures seen with increases in height [27]. In a recent publication, Akam-Venkata et al demonstrated that restrictive lung physiology is associated with exercise capacity independently of height and age at TOF repair. Height was considered a surrogate for spinal deformities, which were prevalent in the study, and could contribute to diminished FVC [8]. In our study, FVC was associated with the outcomes mVO₂% and HRR, however, its association with HRR was confounded by the number of sternotomies, although the direction of the association was maintained in the model. Thus, there seems to be common pathway between restrictive lung physiology, prior sternotomies, and rib cage abnormalities (as suggested by Akam-Venkata), which influences exercise performance. Contrary to our findings, other studies have not shown a correlation between aerobic capacity and resting spirometry measures despite abnormal resting spirometry [27,29,38]. Interestingly, the subset of patients that reached a maximal effort have a higher HRR than the sub-maximal group, therefore, FVC was the only factor associated with mVO₂%, and HRR does not affect mVO₂ in this group, but it does affect mVO₂ in the sub-maximal effort group.

In adults with rTOF, pulmonary artery vascular function is abnormal and is associated with worse exercise performance [41]. During exercise, there is a normal physiologic vasodilation of the pulmonary vascular bed to allow for increased pulmonary blood flow and a consequent relative decrease in pulmonary vascular resistance and RV afterload [42]. Therefore, the characteristics of the pulmonary vascular bed in rTOF could play an important role during exercise. We propose that better FVC in rTOF may indicate a larger pulmonary bed and therefore greater potential for vasodilation, decreased pulmonary vascular resistance and better alveolar recruitment during exercise. While this hypothesis requires validation, it is possible that RV afterload falls further in individuals with better FVC with consequent increase in net RV forward flow during exercise and improved LV preload leading to superior exercise performance. In our study, VE/VCO₂ at anaerobic threshold was not associated with %mVO₂ indicating that gas exchange efficiency is not a significant contributor to exercise performance in this cohort. Thus, our findings suggest that pulmonary function, as measured by FVC, in addition to routine cardiac functional assessment, is an important variable to follow in rTOF.

There is increased risk for impaired lung function and restrictive lung physiology with earlier surgical interventions, multiple cardiac surgeries and multiple thoracotomies independent of CHD complexity and other risk factors [43–45]. As we have shown, the limitation of FVC is associated in part with the number of prior surgical interventions, and contributes significantly to impaired exercise capacity in these patients. We found that FVC, forward flow in the main pulmonary artery (indexed to body surface area) and ability to reach maximum effort were independently directly associated with HRR. FVC was associated with HRR prior to adjusting for number of sternotomies suggesting that while this association exists, there may be a link between restrictive lung physiology and prior sternotomies which influences exercise performance. A possible explanation for the association of FVC and HRR is that patients with reduced FVC may be limited by a small pulmonary vascular bed and during exercise, have greater RV afterload resulting in a drop in stroke volume and inability to reach a higher maximal heart rate, possibly due to abnormal autonomic function and neurohormonal activation, as suggested by other studies in congenital heart defects [35,36,46]. We found no association between RV ejection fraction or RV size with HRR suggesting that pulmonary function, rather than cardiac function, is associated with chronotropic reserve in rTOF. Contrary to our findings, a study by Meadows et al in young adults with TOF demonstrated that the only factor on cardiac magnetic resonance imaging associated with percent predicted oxygen consumption was right ventricular ejection fraction. This discrepancy in findings is likely due to important differences in the TOF populations studied regarding age and range of ejection fraction [47].

In summary, our data would support the concept that reduced pulmonary capacity limits the ability of the RV to maintain adequate stroke volume and cardiac output at higher levels of exercise thus also limiting LV preload under these circumstances. These factors result in limiting exercise performance at lower heart rates resulting in a lower measured HRR.

There are limited data evaluating the relationship between pulmonary function and chronotropic response in CHD. Abnormal pulmonary function as measured by spirometry is associated with increased cardiovascular risk in the adult population with acquired heart disease. It has been proposed that this may reflect the presence of chronic obstructive pulmonary disease (COPD) and a relationship between chronotropic incompetence and reduced exercise performance in patients with COPD, has been described in the adult population [48]. This mechanism has also been proposed in Fontan and TOF patients as well [49]. A blunted heart rate response in COPD has been associated with worse exercise capacity and increased disease severity [50]. Patients with hyperinflation have been shown to have impaired left ventricular diastolic filling and RV dysfunction which may result in effects on stroke volume and cardiac output as well as heart rate [51,52]. It is possible that a similar relationship between pulmonary abnormalities in rTOF and chronotropic incompetence exists.

We also found that net forward flow in the main pulmonary artery was associated with HRR in our study cohort. In a prior study of patients with rTOF undergoing stress echocardiography we found that a decrease in pulmonary insufficiency with increasing heart rate at peak exercise was associated with better exercise performance [11]. The relationship between net forward flow in the main pulmonary artery and HRR suggests a decrease in pulmonary insufficiency during exercise with increasing heart rate and subsequent improved RV output. Similar findings have been demonstrated in adults with rTOF during exercise with increased heart rate and decreased pulmonary insufficiency resulting in increased RV forward flow on CMR [53].

Presence of a genetic syndrome was associated with worse exercise performance in our study, as has been previously shown [54]. In particular, 22q11.2 deletion syndrome and exercise performance have been shown to be mediators of health status and quality of life in rTOF patients [5]. Therefore, understanding the determinants of exercise capacity and potentially intervening to improve exercise performance could also play a role in improving quality of life in patients with rTOF, particularly in those with 22q11.2 deletion syndrome, a prevalent association with TOF. Interestingly, we did not find 22q11.2 deletion syndrome to be independently associated with HRR on multivariable analysis, and thus its effect on exercise performance probably occurs through other mechanisms [55].

In the sub-group of patients with habitual exercise data (n = 69), better FVC and more frequent habitual exercise were independently associated with greater %mVO₂. We found that MPA net forward flow was associated with HRR independently of habitual exercise. It is possible that increased physical activity may play a role in improved pulmonary function resulting in overall better exercise performance regardless of cardiac status. Our findings open potential avenues for intervention, such as exercise rehabilitation programs to improve performance.

This was a large single center study with prospective data collection including all types of rTOF. Accordingly, these results may not be generalizable to all patients but perhaps to those followed at large tertiary care centers and to patients that undergo TOF surgical repair with a transannular patch. The degree of RV dilation was overall mild in the study group and therefore our findings may not be applicable to patients with rTOF and more significant RV dilation. There was a significant number of patients that achieved a sub-maximal exercise test. Given the overall young age of the study cohort, this could be reflective of incomplete effort rather than reflective of exercise capacity and we are not able to discern between these possibilities in this analysis. The habitual exercise data were obtained retrospectively and in a smaller number of patients. This study was a cross sectional analysis and therefore we were unable to evaluate longitudinal changes in exercise performance, pulmonary function and chronotropic response. In addition, we can only establish associations with our results, but not causality.

Our findings suggest that aerobic exercise in patients with rTOF is not limited primarily by cardiac factors such as ventricular function or pulmonary insufficiency but rather by pulmonary function and chronotropic response. Chronotropic response is important in patients that do not reach maximal effort on exercise testing. Evaluation of pulmonary function by spirometry may be an important parameter to assess in rTOF. Interventions such as exercise rehabilitation programs to improve pulmonary health and chronotropic response may potentially improve exercise performance. Interventional studies are needed to establish causality in these relationships and to evaluate results of possible therapies to improve exercise capacity in this population.