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International Journal of Cardiology 161 (2012) 68–72
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International Journal of Cardiology
journal homepage: www.elsevier.com/locate/ijcard
Review
The role for cardiopulmonary exercise testing in patients with atrial septal defects:
A review
Anthony J. Barron ⁎, Roland Wensel, Darrel P. Francis, Iqbal Malik
International Centre for Circulatory Health, Imperial College London and Imperial College NHS Trust, UK
a r t i c l e
i n f o
Article history:
Received 23 July 2011
Received in revised form 31 August 2011
Accepted 5 September 2011
Available online 28 September 2011
Keywords:
Atrial septal defect
Cardiopulmonary exercise testing
Exercise Physiology
a b s t r a c t
Secundum atrial septal defects (ASD) are the commonest congenital cardiac abnormality. They are often
identified incidentally, or in conjunction with an acquired cardiac abnormality. Untreated they may lead to
significant morbidity and mortality, with consequences including right ventricular overload and right heart
failure, pulmonary arterial hypertension, shunt reversal and cyanosis, and arrhythmias. Deciding whether
to close an ASD can consume as much clinical time as finding them or indeed closing them. In the past
when surgical closure was the only option, the morbidity of the procedure, including the need for sternotomy
or thoracotomy, limited its use to large defects considered likely to result in shunt reversal or heart failure.
Smaller defects were often managed conservatively. However within the past 2 decades percutaneous closure has come to the fore and is now considered first line when morphology allows. With lower morbidity,
this has “lowered the bar” in terms of who is considered for closure, although the absolute mortality risk
of either procedure is low. However, even though mortality is low, morbidity is still significant after percutaneous closure. Despite this, the utilisation of ASD closure has dramatically increased in the last decade with a
sudden rise from 2001, owing largely to growth in percutaneous closures. Instead of looking for symptoms,
which are subjective, or evidence of large shunt/RV failure, an objective measure of exercise capacity might
help identify other patients who would benefit from closure. This review will look at the current evidence
of cardiopulmonary exercise testing (CPET) in ASD closure.
© 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Secundum atrial septal defects (ASD) are the commonest congenital cardiac abnormality with an adult incidence of 1 in 5,000–10,000
[1,2]. They are often identified incidentally, or in conjunction with an
acquired cardiac abnormality. Untreated they may lead to significant
morbidity and mortality, with consequences including right ventricular overload and right heart failure, pulmonary arterial hypertension
(PAH), shunt reversal and cyanosis, and arrhythmias. Deciding
whether to close an ASD can consume as much clinical time as finding
them or indeed closing them.
In the past when surgical closure was the only option, the morbidity of the procedure, including the need for sternotomy or thoracotomy, limited its use to large defects considered likely to result in shunt
reversal or heart failure. Smaller defects were often managed conservatively. However within the past 2 decades percutaneous closure
has come to the fore and is now considered first line when morphology allows [3]. With lower morbidity, this has “lowered the bar” in
terms of who is considered for closure, although the absolute
⁎ Corresponding author at: Office of Dr Francis, International Centre for Circulatory
Health, Imperial College London, 59 North Wharf Road, London W2 1LA, UK. Tel.:
+ 44 207 594 1093; fax: + 44 207 594 1706.
E-mail address: [email protected] (A.J. Barron).
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2011.09.006
mortality risk of either procedure is low. However, even though mortality is low, morbidity is still significant after percutaneous closure;
with adverse events of 8.2% during admission in one study [4], and
long-term complications such as erosion which may necessitate
long-term follow-up to detect. Despite this, the utilisation of ASD closure has dramatically increased in the last decade with a sudden rise
from 2001, owing largely to growth in percutaneous closures (surgical rates remained reasonably static) [5]. It is unlikely that ASD prevalence has changed, so this increase in closure likely represents either
increased detection through improved imaging techniques or the
consideration of closure in patients with less severe ASDs.
Instead of looking for symptoms, which are subjective, or evidence
of large shunt/RV failure, an objective measure of exercise capacity
might help identify other patients who would benefit from closure.
This review will look at the current evidence of cardiopulmonary exercise testing (CPET) in ASD closure.
2. Background
In a large analysis of over 15,000 closures, of which 35% were percutaneous, overall mortality rate for surgical closure was 0.88%, and
for percutaneous closure 0.60% (no significant difference) [5]. However the two groups were not similar, with an average of age of 27 and
42 years respectively and co-existent cardiac abnormalities in 3% and
A.J. Barron et al. / International Journal of Cardiology 161 (2012) 68–72
69
1% respectively. It is unclear whether age at closure affects outcome,
with some suggesting that patients surviving past 40 years are likely
to have self-selected as a low risk group. However, in a study of late
closure (all patients above 40 years with pulmonary to systemic
flow ratio (Qp:Qs) ≥1.7 and 25% with arrhythmias at entry) there
were twice as many primary end-points (which included major cardiovascular events, infections, progression of pulmonary hypertension, arrhythmias and cardiovascular mortality) reached in the
medical group compared to patients that underwent surgery [6].
Mortality was non-significantly increased in the medical group.
Heart failure and arrhythmia dominate the picture in older patients
undergoing ASD closure, especially in patients with raised pulmonary
pressures, and cause the majority of late mortality [7]. Atrial arrhythmia after the procedure is almost exclusively noted in patients with
arrhythmias prior to closure [8,9] and post-closure risk is reduced,
in particular the risk of atrial fibrillation [10,11]. In patients undergoing closure, symptoms and raised pulmonary pressures are commoner in older patients with similar improvements in pressures, RV size
and symptoms after closure in the older patients [12]. This was not
a randomised trial of closure versus medical therapy however, and
it is very possible that older patients had more stringent recruitment
criteria, making it more likely that they had more advanced disease as
only the more severely affected were intervened upon.
Questions remain over whether this is truly a procedure for all
ASDs. Is there a group that does not derive benefit, and if so, can we
identify them?
To decide if benefit occurs, especially in smaller ASDs that are less
likely to affect mortality (especially during short-term follow-up)
surrogate markers of improvement are needed. For example right
heart dimensions, measured through echocardiography, have been
shown to improve following closure [13].
Table 1
Summary of main parameters derived from a cardiopulmonary exercise test.
3. Cardiopulmonary exercise test parameters and diagnosing a
right-to-left shunt
16]. As pulmonary vasculopathy progresses, flow mediated dilatation
of the pulmonary artery cannot increase appropriately and pulmonary arterial resistances go up during exercise. Therefore exercise
progressively favours shunting from right to left; initially the volume
of left-to-right shunting seen at rest decreases, and potentially a reversal of the shunt could occur at peak exercise (Fig. 1a–e). The cardiopulmonary responses at the onset of exercise in healthy controls
have been well described [17–19]. There is a sudden increase in oxygen consumption and a similar (but slightly smaller) rise in carbon dioxide production leading to a small fall in the respiratory exchange
ratio (RER). Ventilation increases to a lesser extent. Because of this
CPET has been established for many years to help identify severity
and cause of functional limitation. A patient is exercised, usually with
work becoming incrementally harder, on a treadmill or bicycle ergometer. During rest, exercise and recovery the patient breathes
through a mouthpiece or mask, where oxygen consumption and carbon dioxide production, as well as air flow at the mouth are measured
and other variables calculated. The main parameters identified on
CPET are described in Table 1. The principal parameter, peak VO2 –
sometimes erroneously referred to as VO2max – is the amount of oxygen consumed by the body at the peak of tolerable exercise. It is reduced in most pathological conditions and reduction is associated
with worsening of prognosis across multiple cardiopulmonary conditions. There is often inefficiency of gas exchange in the lung in cardiac
disease, including ASD, which is seen by raised ventilatory equivalents, i.e. the VE/VO2 and VE/VCO2 ratios. These are the volume of
ventilation required to uptake or excrete 1 L of O2 or CO2 respectively,
and high values are abnormal. The O2 pulse, the amount of oxygen
consumed per heart beat, which is considered a surrogate for stroke
volume, and the anaerobic threshold (the VO2 when anaerobic metabolism is required to maintain work), will also be reduced in cardiac
disease, including ASD. Although peak VO2 alone is not specific
enough to determine cardiac limitation over other conditions, such
as respiratory disease, obesity and deconditioning which also all
lower peak VO2, the use of the other parameters described allows
for an estimation of the impact of the ASD in patients with multiple
co-morbidities.
CPET can also be used to diagnose a right-to-left shunt [14–16].
Evidence from patients with other congenital heart disease or patients with pulmonary hypertension (PAH) and a patent foramen
ovale (PFO), show that the response of the arterial oxygen saturations
and end-tidal CO2 (PETCO2) can diagnose a right-to-left shunt [14–
CPET parameter
Description
Peak VO2
Maximum oxygen consumption (VO2) obtained during
an incremental exercise test.
Maximum oxygen consumption possible by that patient
at that exercise. It requires a plateau in oxygen
consumption despite increases in workload. Analogous
to peak VO2 if effort was maximal but practically is
rarely achieved by patients.
The point at which oxygen delivery to the muscles fails
to meet 100% of the demand, requiring anaerobic
metabolism to supplement energy requirements. Also
known as lactate threshold/ventilatory anaerobic
threshold.
Ratio of carbon dioxide production to oxygen
consumption. As anaerobic metabolism intervenes
excess CO2 relative to O2 is produced through buffering
of lactic acid; an RER rising to N1 is a sign of
reasonable effort.
The number of litres of air breathed (VE) required to
eliminate 1 L of CO2 or uptake 1 L of O2. Expressed as a
ratio at a single point in time, or as a regression slope of
the change during exercise. Value increases as
ventilatory efficiency or dead space worsens.
The oxygen consumed per heart beat. Equals the
product of stroke volume and arterial-venous oxygen
difference. The latter almost always behaves
consistently, allowing the O2 pulse to act as a
surrogate for stroke volume.
The partial pressure of O2 or CO2 at the end of
expiration, the point when equilibrium with arterial
blood is closest. Changes usually reflect equivalent
changes in arterial
concentrations of O2 and CO2.
VO2 max
Anaerobic threshold (AT)
Respiratory exchange ratio
(RER)
Ventilatory efficiency
(VE/VCO2 and VE/VO2)
O2 pulse
End-tidal O2/CO2
(PET O2/CO2)
Fig. 1. Changes in flow across an ASD during progression of pulmonary vasculopathy.
a) Initially the shunt is of large volume and left-to-right. b) Initial changes to the pulmonary vasculature causes a rise in right atrial pressure and a decrease in the volume
of blood shunting to the right atrium. c) As pulmonary vasculopathy worsens,
left-to-right shunting at rest still occurs. d) However reversal may occur on exercise.
e) Finally Eisenmenger's physiology intervenes even at rest with right-to-left shunting.
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relative hypoventilation, PETO2 decreases and PETCO2 increases. Saturations remain constant. In contrast, in patients with right-to-left
shunts, as an increased degree of deoxygenated venous blood shunts
to the left system due to rising pulmonary and right atrial pressures,
saturations typically fall, and continue to fall throughout exercise.
This disproportionate rise in CO2 levels in the arterial circulation
elicits a reflex increase in ventilation larger than would be expected
for that level of CO2 production; this leads to a decrease in PETCO2,
and by the same mechanism, an increase in PETO2. This typical exercise response appears to occur even in patients without resting pulmonary hypertension [15].
Patients with small ASDs and a near normal Qp:Qs (1.0–1.5),
with no pulmonary vascular remodelling at rest or on exercise may
not behave like this, and may adopt a pattern typical of healthy
controls.
It is important to point out that these findings will happen in any
condition leading to a right-to-left shunt, and are not specific to an
ASD. Systematic data are lacking as to the relevance of shunt reversal
identified on CPET, however, it could potentially be useful in identifying
patients who would not benefit from closure, who may rely on shunt reversal to maintain cardiac output during exercise, given that atrial septostomy is an accepted practice for pulmonary hypertension. However
the practice of not considering closure in patients with established
shunt reversal also has its doubters. PDE-5 inhibitors such as sildenafil
have been shown to reduce right sided pressures and desaturation in
patients with ASD and pulmonary hypertension [20,21], and in a cohort
of patients with Eisenmengers syndrome principally due to ASD [22].
Similarly patients treated with endothelin-receptor antagonists such
as Bosentan have shown reduction in symptoms and pulmonary
pressures, but without significant increases in arterial oxygen
saturations [23]. Evidence with long-term prostacyclin therapy are
limited mainly to case reports [24]. It is possible that re-reversal of the
shunt could occur if pressures were reduced sufficiently to allow reinitiation of a left-to-right shunt. Although randomised-controlled trials
on vasodilator therapy before and after closure have not yet been performed, there are numerous case reports in the literature of patients
successfully treated with sildenafil [25], bosentan [26] or intravenous
prostacyclin [26,27] allowing for defect closure.
4. Exercise capacity prior to ASD closure
On average, patients with ASD have an objective exercise capacity
35–39% below normal [28,29], but may learn to live with this or be
unaware. Hence, even patients who describe themselves as asymptomatic turn out to have an objective exercise capacity more than
25% below normal [30,31] with peak VO2 lowest in patients with
symptoms compared to those without [32]. Other CPET parameters
involving gas exchange efficiency and the anaerobic threshold are
also impaired in patients with ASD [29,30]. There have been no systematic studies utilising serial CPET on patients with ASD managed
conservatively, however it was established in an early cross-sectional
study that symptoms usually develop during adulthood and older patients were more frequently disabled by symptoms suggesting the
natural time course is far from benign [33]. What these early studies
cannot tell us is the progression of disease in the patients found to
have ASD as an incidental finding, once a rare occurrence but now a
relatively common finding with the greater access to echocardiography and superior imaging quality of today.
ASD causes abnormalities in invasive haemodynamics at rest. However the degree of these resting abnormalities does not always correspond to the degree of interference with exercise capacity as shown
by objective measurements such as peak oxygen uptake [34–37]. The
same is found with the pulmonary to systemic flow ratio, Qp:Qs,
which correlates to peak VO2 pre-closure in three studies [30,31,36]
but not in three others [38,29,32].
5. Functional improvements following closure
5.1. Surgical closure
RV dimensions change dramatically after ASD closure [13]. Objective exercise capacity almost doubles (reaching normal values) in the
long term after surgical closure of an ASD [38], although this improvement is gradual and only a very small proportion of it is seen in the
first few months. Other studies have shown significant but less dramatic improvements, but only assessed patients within the first
18 months [37,42]. Interestingly in one study there was a significant
improvement seen in all patients except those with established resting pulmonary hypertension (systolic pulmonary pressures greater
than 50 mm Hg) and a Qp:Qs less than 3 [37]. Similarly patients
with haemodynamic abnormalities but low Qp:Qs ratios did not derive benefit in exercise capacity after surgical closure, although this
study did perform the post-intervention CPET earlier than comparative studies (mean 4.6 months). It is conceivable that this represents
patients in which “Eisenmenger's physiology” has intervened as evidenced by Qp:Qs ratios below that expected from the size of the defect. Have these patients “missed the boat” or will they just require
a longer period of recovery before improvement will be seen on
CPET? Although they may not show functional improvement, it is
possible that the procedure will slow or halt further deterioration
and prevent future morbidity.
5.2. Percutaneous Closure
The first small study of patients following percutaneous closure
showed no significant difference in peak VO2, anaerobic threshold
and oxygen pulse [35]. Larger studies show significant improvements
in peak VO2 occur amongst patients who were either asymptomatic
or mildly symptomatic [31,32] and patients with symptoms, significant RV adverse remodelling or raised pulmonary pressures [39]. Interestingly, even patients with “normal” peak VO2 pre-intervention
showed significant improvements to levels above normal; these
gains in peak VO2 were similar in magnitude to the rest of the cohort,
i.e. everyone, regardless of baseline functional capacity, improved to a
similar degree after closure [32]. Significant improvement can occur
as early as 3 months, earlier than seen in comparable surgical studies
and probably relates to the decreased recovery times seen after percutaneous closure.
These improvements appear to continue over time with improvement at 6 months and significant further increases at 3 years (peak
VO2 61.8%, 72.6% and 88.8% predicted at baseline, 6 months and
3 years respectively) [40]. Few patients had a peak VO2 within normal
limits at baseline (10%) compared with 28% at 6 months and 79% at
3 years. This study also showed continuous improvements in the O2
pulse and markers of improved pulmonary gas exchange. Patients
with greater shunt volumes showed relatively better long-term improvement [39]. Neither age [32,39] nor baseline NYHA class [32]
seems to affect the size of the benefit to improved peak VO2 following
ASD closure. Improvements in peak VO2 seen with closure are significant and of a generally large magnitude, even accounting for the
“familiarisation effect” of repeated CPET [41] and appear to be independent of the modality of closure [42]. Thus ASD closure appears
to be a reasonable therapeutic option at any age.
5.3. Who benefits from closure
Patients with an ASD can broadly be categorised into four groups,
some with clear indications for closure, and others less so. How these
four groups relate to one another can be seen in Fig. 2.
1. A substantial shunt (Qp:Qs N1.5) with no signs of pulmonary vasculopathy (i.e. normal tricuspid regurgitation velocity without
A.J. Barron et al. / International Journal of Cardiology 161 (2012) 68–72
71
pulmonary vasculopathy with shunt reversal on exercise, where closing
the shunt may be detrimental. Cardiopulmonary exercise testing could
be useful in the former to identify if a patient is truly asymptomatic, and
to identify shunt reversal in the latter when resting haemodynamics
may not be helpful. It may be possible in the future to use it to identify
those patients who would not gain benefit.
Funding sources
DPF was supported by the Senior Clinical Fellowship programme
of the British Heart Foundation (FS/04/079). The authors' institution
receives funding support from the National Institute for Health Research (NIHR) biomedical research centre scheme.
Disclosures
Fig. 2. Applicability of CPET in relation to defect size, shunt size and risk of developing
pulmonary vasculopathy. Group 4: small defects with a low Qp:Qs ratio (1.0–1.5) and
low risk of development of pulmonary vasculopathy. Group 1: Larger defect and Qp:Qs
ratio at risk of developing pulmonary vasculopathy although this is not present at the
time of testing. Group 3: Large defect with falling Qp:Qs ratio as pulmonary vasculopathy develops, but no shunt reversal at rest. Group 2: Severe pulmonary vasculopathy
with shunt reversal, therefore a Qp:Qs ratio below 1.0, this is Eisenmenger's
physiology.
severe regurgitation, normal right ventricular size and function,
normal pulmonary arterial size, and no signs of shunt reversal as
seen by desaturation on exercise). There is little doubt that closure
would be of benefit in this group, both to prevent mortality and
morbidity, and to improve symptoms.
2. Shunt reversal at rest (Qp:Qs b1.0) due to severe pulmonary hypertension as in these patients the ASD acts as a pressure reliever
and closure may precipitate right ventricular failure. Targeted
PAH therapy may be more appropriate at this stage [3,43]. CPET
is unlikely to add further clinically relevant data and recent guidelines (ACC/AHA 2008) consider severe pulmonary hypertension as
a contraindication for symptom limited CPET [44].
3. A shunt volume disproportionately small for the size of the ASD,
with evidence of pulmonary vasculopathy. This group lies somewhere between the first two groups, and it would seem reasonable
to close if there was no evidence of shunt reversal during exercise.
CPET would be useful to identify exercise induced shunt reversal.
4. Small ASD and low Qp:Qs (1.0–1.5). Currently RV dilatation is used
as a surrogate marker for risk. If the RV is not dilated, should we
leave alone? There is minimal evidence to suggest this group benefits
from closure and a prospective study would be worthwhile. Reduced
exercise capacity on CPET could be useful to decide on who requires
closure. Serial measurements could also be used in follow-up when
baseline values are within normal limits to identify when deterioration occurs. Routine CPET follow-up is recommended for all congenital heart disease in the new ESC guidelines for management of
Grown-Up Congenital Heart Disease [3]. The ACC/AHA guidelines
specifically suggest the use of CPET in patients where symptoms
may be discrepant with clinical findings, for example this group
with small defects. This is level C evidence, accepting the limited experience of serial CPET testing in patients prior to intervention [44].
6. Conclusions
The majority of patients with atrial septal defects have impairment of exercise capacity as evidenced on cardiopulmonary exercise
testing, even if they describe themselves as asymptomatic. Closure
leads to an increase in functional capacity which appears sustained
and may even continue to improve over long-term follow-up, with
patients deriving benefit regardless of age and baseline symptom
status.
However amongst certain groups there still remains doubt; asymptomatic patients with very small shunts and those with established
The authors have no conflicts of interest to declare.
Acknowledgements
No other persons have made substantial contributions to this
manuscript.
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