Atrial septal defect and exercise capacity: value of cardio-pulmonary exercise test in assessment and follow-up
Nearly four decades ago, the World Health Organization stated that functional capacity explorations best reflected the impact of a chronic disease on quality of life (1). In chronic heart failure, several studies have demonstrated a correlation between maximal oxygen uptake (VO2max) and both quality of life and prognosis (2-4). Similar results have also been found in patients with congenital heart diseases (CHDs) (5-9) and cardio-pulmonary exercise test (CPET) is now recommended in the follow-up of this population (10).
Atrial septal defects (ASDs) represent the second most frequent CHD, with a worldwide reported birth prevalence of 2.6 per 1,000 live births (11). Undiagnosed ASDs remain significant in paediatrics (12) and their incidence in adulthood reaches the rates of 1 in 5,000–10,000 (13). Before the 90’s, cardiac surgical repair was the only option for ASD; therefore, only large defects with significantly increased pulmonary blood flow (Qp/Qs >2) underwent heart surgery. Nowadays, percutaneous catheter closure is the first line therapy for most patients with ostium secundum ASDs (10). Indications of ASD closure have been progressively extended to smaller defects, ASDs with moderate pulmonary hypertension, elderly patients, and younger children (14).
Exercise capacity of patients with unrepaired ASDs depends on the importance of the shunt, the right ventricular (RV) function and volume overload, the level of pulmonary arterial pressure, and the occurrence of arrhythmias. For repaired ASDs, exercise capacity also depends on the delay before closure and the type of procedure (catheter or surgery) (15).
This review focuses on the value of CPET in assessment and follow-up of patients with repaired and unrepaired ASDs.
We searched three electronic databases on October 2017 (PubMed, EMBASE, and Web of Science) by using a combination of the terms “atrial septal defect” and “exercise test”. We also used the terms “cardio-pulmonary exercise test” “CPET”, “VO2” “maximum oxygen uptake” “ASD” “peak VO2” “VO2max” in combination. The selection criteria were as follows: CPET assessment at diagnosis, CPET follow-up after ASD device closure or surgical procedure, CPET follow-up of complications (pulmonary hypertension, arrhythmia, and heart failure) and articles written in English. We did not set any restriction to study setting, era, or locale. Paediatric and adult patients were eligible. In title and abstract screening, two reviewers (P.A. and A.G.) independently reviewed articles identified by the search. Studies identified in title or abstract screening were included for full-text review.
We selected 32 original studies and 2 review articles. One article in Polish and one in German were not selected (16,17). Most studies did not detail the maximum exercise test criteria and/or the existence of a plateau of VO2. Therefore we purposely referred to “peak VO2” in this review. The main CPET parameters are reported and explained in Table 1 (18). The value of these parameters in repaired and unrepaired ADS are summarized in Table 2.
CPET in unrepaired ASDs
In most reported studies, patients with ASDs have an impaired exercise capacity and their VO2max is reduced until 60% of predicted values and decreases with age (19-24), including minor reduction even for asymptomatic patients (25). Despite the lack of longitudinal cohort CPET studies among ASD patients, it is well established that symptoms usually appear during adulthood and may compromise exercise capacity in older patients (26).
However, the link between peak VO2 and invasive haemodynamic evaluation at rest [mean pulmonary arterial pressure (mPAP), Qp/Qs ratio] remains unclear (27-30). Some studies found a correlation between Qp/Qs and peak VO2 (21,22,29), whereas some others did not (20,25,31).
In ASD patients, RV function may also represent a limiting factor. Indeed, physiologically, the RV mean power is defined as the product of RV cardiac output by mPAP) and is linearly correlated to peak VO2. Van De Bruaene et al. have shown that, compared to healthy controls, the workload of the RV in patients with an open ASD was higher at rest, due to a left-to-right shunt, and at peak exercise, due to an additional increase in mPAP (32). Therefore, during exercise, a higher increase in RV afterload may affect its function, even in asymptomatic ASD without volumetric overload and normal RV function evaluated at rest (33).
Other CPET parameters may be altered in ASDs. The ventilatory efficiency measured by the VE/VCO2 slope increases in ASDs associated with heart failure, RV dysfunction, pulmonary hypertension and/or lung disease (18,20,21,23). The VE/VCO2 slope correlates to prognosis in heart failure (34) and needs to be monitored in the follow-up of CHD patients, as now recommended (10).
The ventilatory anaerobic threshold (AT) may also be impaired in ASDs, as a result of muscular deconditioning, like many patients with simple and complex CHD (8). The “vicious circle” of deconditioning includes dyspnoea at exercise, sedentary lifestyle, overweight and a lack of motivation for sports and exercise. Yet, physical activity and sports are in most cases authorized and even recommended in ASDs (35). Restrictions only concern scuba diving in the presence of a small shunt (risk of paradoxical air emboli), competitive sports in case of symptomatic atrial or ventricular arrhythmias and high intensity sports in case of pulmonary arterial hypertension (PAH) (pulmonary arterial systolic pressure >40 mmHg) (36). Therefore, in the situation of muscular deconditioning diagnosed by CPET, cardiac rehabilitation may be considered for ASD patients (4,37,38).
CPET in repaired ASDs
The large majority of reported studies found a significant improvement in exercise capacity after ASD closure, with both surgical and catheter procedures (15,39). The peak VO2 gradually improves after the procedure (30,40-42), and sometimes reaches normal values in the long term (31). Only one study found no improvement of peak VO2, anaerobic threshold and oxygen pulse after ASD catheter closure, but the cohort was small (N=9) and the delay after procedure was limited, between 1 and 7 months (28).
Once the ASD is closed, the reduction of volumetric overload is associated with a rapid RV remodelling (≅1 month after the procedure) and a significant exercise capacity improvement (≅6 months after the procedure) (40,41,43,44). Along with the peak VO2, the anaerobic threshold, the ventilatory parameters and the oxygen pulse also improve after ASD closure (42,45). At exercise, the stress-induced pulmonary hypertension reduces, the RV means power increases and the RV strain improves (32,46,47). The improvement in terms of exercise capacity after ASD closure concerns patients of all ages, even elderly ones (40,43,48), but is more marked when the procedure occurs at an early stage during childhood (49). However, even when ASD closure is performed in childhood, some patients may have RV strain anomalies more than three decades after the procedure (50). Therefore, CPET remains useful in the long-term follow-up for all patients with a history of ASD.
The haemodynamic status before ASD closure stands as a main determinant for the exercise capacity improvement after the procedure. Indeed, exercise capacity in patients with large left-to-right shunt increases after ASD closure regardless of whether they had high pulmonary arterial pressure (30).
Interestingly, even asymptomatic patients and patients with sub-normal peak VO2 before ASD closure seem to improve their exercise capacity after the procedure (22,25). Similarly, some patients with insignificant shunt (Qp/Qs <1.5) may also benefit from ASD closure in terms of peak VO2, oxygen pulse, ventilatory efficiency and quality of life (45). Indeed, a normal haemodynamic status at rest in patients with ASDs might not be predictable of a normal haemodynamic adaptation at exercise.
No randomized trial compared catheter and surgical ASD closures in terms of CPET parameters’ variation. However, the observational study from Suchon et al. reported a higher decrease in VE/VCO2 slope after catheter than after surgical closure, at 1-year follow-up (39). Similarly, Van De Bruaene et al. showed a gap of 18% in terms of ventilatory efficiency between surgically treated patients and healthy controls, more than 7 years after surgery (23). Physiologically, pulmonary hyper perfusion may deteriorate the lung viscoelastic properties, resulting in remodelling of the lung parenchyma and fibrotic changes (51-53). In this context, the age at cardiac surgery appears to be determinant for the lungs’ ability to preserve or regain their compliance (49).
CPET and comorbidities related to ASDs
As discussed in the previous paragraph, heart failure, PAH and arrhythmia are the main complications of repaired or unrepaired ASDs, for which CPET may be useful.
The existence of an impaired exercise capacity after ASD closure may be associated with RV dysfunction and/or abnormal vascular pulmonary response to exercise (54). For instance, patients with a moderate left-to-right shunt (Qp/Qs <3) associated with elevated pulmonary arterial pressure (systolic PAP >50 mmHg) have an impaired peak VO2, which might not improve after ASD closure (30).
In patients with mild tricuspid insufficiency observed after ASD closure, the exercise capacity is more reduced. Mild tricuspid insufficiency occurs more frequently in older patients and in patients with higher mPAP at peak exercise (55). It could be considered as a marker of subclinical persistent diastolic pressure load on the right ventricle, even after ASD closure.
The exercise capacity is impaired in case of RV dysfunction, as a result of early and/or prolonged RV volume overload, but possibly also as sequel of surgery (50).
A right-to-left shunt at exercise will lead to desaturation and decrease in PetCO2. Therefore, CPET may identify patients who would benefit or not from ASD closure, regarding the risk of developing pulmonary arterial vasculopathy (15). Indeed, the deoxygenated venous blood shunting to the systemic circulation causes a disproportionate rise in CO2 levels and a reflex increase in ventilation (18). This condition commonly occurs in PAH with patent foramen ovale (PFO). Patients with PAH associated with ASD have an important decrease of exercise capacity associated with hyperventilation, attested by a VE/VCO2 ratio increase. Indeed, in the most severe physiology, i.e., the Eisenmenger syndrome, the peak VO2 is the lowest and the VE/VCO2 slope the highest among all CHDs (8). As a result, the quality of life of these patients is significantly impaired, especially in the physical well-being, with a strong correlation to their NYHA functional class (56).
For patients in the “grey zone” of PAH, i.e., pulmonary vascular resistance between 2.3 and 4.6 Wood Units (57), ASD closure remains under debate. Some patients have been successfully treated with sildenafil, bosentan or intravenous prostacyclin allowing for defect closure (58-60). However, randomized-controlled trials on vasodilator therapy before and after ASD closure in such physiological conditions are lacking. Therefore, CPET parameters (VO2max, VE/VCO2 slope) would probably be useful as primary or secondary outcomes in future clinical trials.
Atrial fibrillation (AF) is the most common arrhythmia associated with ASD. In a large cohort of 1,111 ASD patients diagnosed during childhood, Karunanithi et al. showed an significantly increased risk of AF; both with closure [adjusted hazard ratio (HR) 18.5; 95% CI: 7.8–44.1, P<0.0001] and without closure (HR 16.4; 95% CI: 6.8–39.8; P<0.0001), in comparison with controls. A comparison of surgical closure with transcatheter closure found no difference in terms of risk of AF (61). Classically, the AF needs to be reduced before CPET is performed. However, in case of chronic AF associated with ASD, CPET parameters are not specific, showing deterioration of peak VO2, oxygen pulse, VE/VCO2 slope, and heart rate response (62).
Abnormal heart rate response during exercise is uncommon in ASDs, however, chronotropic incompetence may occur after surgical repair and therefore be diagnosed by CPET (63). Moreover, ASDs may be associated to progressive atrioventricular block, related to NK2 homeobox 5 (NKX2.5) mutations (64).
Heart failure in ASDs may also be related to left ventricular (LV) dysfunction. Indeed, some studies have reported deterioration of systolic or diastolic LV function after ASD closure. An acute rise in the volume and filling pressure of both the left atrium and LV may cause left-sided heart failure, even without evident LV dysfunction prior to the intervention (65-67). This rare condition mostly concerns elderly patients and/or patients with a large shunt, for which impairment of LV contractility may occur until 6 months after closure (68). CPET results for LV dysfunction after ASD closure are not specific: decrease in peak VO2, oxygen pulse and anaerobic threshold, and increase in heart rate response and VE/VCO2 slope. Therefore, close long-term observation is required after ASD closure, especially in older patients with a large shunt. In a recent study, the absolute ASD shunt volume per minute remained unchanged under dobutamine stress test compared to values at rest, and the peak VO2 correlated to cardiac output but not to RV volume, suggesting abnormal LV compliance as a limiting factor for exercise capacity (69).
CPET in paediatric patients with ASDs
Exercise intolerance is uncommon in young children with an isolated ASD (28). However, pulmonary function is often impaired in this age group and improves after ASD closure (70). Although exercise capacity seems to insidiously decrease with age, serial CPET studies starting from paediatric age are clearly missing (24). In a small paediatric cohort (N=16), CPET parameters in children with ASD only slightly differ from those in normal children (71). Another small cohort (N=10) found no differences in terms of VO2max between children with ASD and controls (72). Similarly, in a study of 22 children with ASD surgical repair (N=22), Rosenthal et al. found that exercise performance was unaffected by age at repair (73).
Although peak VO2 correlates with the quality of life of children with CHDs (9), the follow-up of paediatric CHD patients with CPET is not yet recommended as it is in adults with CHDs (10). Nevertheless, a normal or sub-normal peak VO2 in such a simple CHD may participate in promoting self-confidence to the child, reassuring his or her family, and motivating them to engage the young patient in physical activity (74). Indeed, although physical activity and sports are in almost all cases authorized in children with ASDs (75), CHD children are often hovered over by their parents, stigmatized by their teachers, and eventually remain on the side-lines (74,76). Consequently, their quality of life is significantly reduced (9,77). Therefore, CPET follow-up in children with ASDs may detect early onset of muscular deconditioning, for which cardiac rehabilitation may be considered (75,78).
The CPET provides important information in assessment and follow-up of patients with ASDs, for both children and adults. In most cases, the exercise capacity is fairly normal and CPET contributes to promote sports participation. Furthermore, a regular CPET follow-up is necessary to evaluate the occurrence, severity and physiological mechanisms of comorbities, i.e., heart failure, pulmonary hypertension and arrhythmia. Finally, CPET follow-up in patients with ASDs may detect early onset of muscular deconditioning, for which cardiac rehabilitation may be considered.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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