Congenital heart disease

Original research

Efficacy of treat-­and-­repair strategy for atrial septal

defect with pulmonary arterial hypertension
Yoichi Takaya ‍ ‍,1 Teiji Akagi,1 Ichiro Sakamoto,2 Hideaki Kanazawa,3
Gaku Nakazawa,4 Tsutomu Murakami,5 Atsushi Yao,6 Mamoru Nanasato,7 Mike Saji,7
Mitsugu Hirokami,8 Yasushi Fuku,9 Shinobu Hosokawa,10 Norio Tada,11
Kensuke Matsumoto,12 Masao Imai,13 Koji Nakagawa,1 Hiroshi Ito1

For numbered affiliations see ABSTRACT Treatments for PAH have dramatically advanced
end of article. Objective Therapeutic strategies for atrial septal defect because of development of PAH-­specific medica-
(ASD) with severe pulmonary arterial hypertension tions, including endothelin receptor antagonists,
Correspondence to
(PAH) are controversial. This study aimed to evaluate the phosphodiesterase type-­5 inhibitors and prostacy-
Dr Yoichi Takaya, Department
of Cardiovascular Medicine, efficacy of PAH-­specific medications and subsequent clins. These medical treatments improve survival in
Graduate School of Medicine transcatheter closure (ie, treat-­and-­repair strategy) on patients with PAH.13 14 Recently, a few studies have
Dentistry and Pharmaceutical clinical outcomes. reported that PAH-­specific medications and subse-
Sciences, Okayama University, quent transcatheter closure (ie, treat-­ and-­
repair
Okayama, Japan;
Methods We enrolled 42 patients who were referred
​takayayoichi@​yahoo.​co.​jp to 13 institutions for consideration of ASD closure with strategy) are effective for ASD with severe PAH.15–18
concomitant PAH and underwent the treat-­and-­repair There has been increasing interest in the potential
Received 29 January 2021 strategy. The endpoint was cardiovascular death or for the treat-­ and-­repair strategy. However, these
Accepted 21 May 2021 data are limited to case reports. Clinical outcomes
hospitalisation due to heart failure or exacerbated PAH.
Published Online First
15 June 2021 Results At baseline prior to PAH-­specific medications, of the treat-­ and-­repair strategy remain unclear.
pulmonary to systemic blood flow ratio (Qp:Qs), Therefore, this study aimed to evaluate the efficacy
pulmonary vascular resistance (PVR), and mean of the treat-­and-­repair strategy on clinical outcomes
pulmonary artery pressure (PAP) were 1.9±0.8, 6.9±3.2 in patients with ASD complicated with PAH.
Wood units and 45±15 mm Hg. Qp:Qs was increased
to 2.4±1.2, and PVR and mean PAP were decreased to
METHODS
4.0±1.5 Wood units and 35±9 mm Hg at the time of
Study design
transcatheter ASD closure after PAH-­specific medications.
This multicentre cohort study involved 13 insti-
Transcatheter ASD closure was performed without any
tutions in Japan. This study enrolled a total of 42
complications. During a median follow-­up period of 33
patients with ASD complicated with PAH, who
months (1–126 months) after transcatheter ASD closure,
were referred to the institutions for consideration
one older patient died and one patient was hospitalised
of ASD closure with concomitant PAH and under-
due to heart failure, but the other patients survived
went PAH-­ specific medications and subsequent
with an improvement in WHO functional class. PAP was
transcatheter closure (treat-­ and-­
repair strategy)
further decreased after transcatheter ASD closure.
between January 2008 and December 2019. All
Conclusions The treat-­and-­repair strategy results in
patients underwent transcatheter ASD closure using
low complication and mortality rates with a reduction in
non-­fenestrated devices. PAH was defined as mean
PAP in selected patients with ASD complicated with PAH
pulmonary artery pressure (PAP) of ≥25 mm Hg,
who have a favourable response of medical therapy.
pulmonary arterial wedge pressure of ≤15 mm Hg
and PVR of ≥3.0 Wood units at cardiac catheteri-
sation. The regimens of PAH-­specific medications
were determined by cardiologists at each institution
INTRODUCTION who specialised in pulmonary hypertension. The
Atrial septal defect (ASD) of secundum type is decision of performing transcatheter ASD closure
a common congenital heart disease. Pulmonary was made on the basis of the patient’s haemody-
arterial hypertension (PAH) occurs in 6%–35% of namics after PAH-­ specific medications. PVR of
patients with ASD1 and is associated with increased <5.0–7.0 Wood units and significant left-­to-­right
mortality and functional limitations.2 Transcatheter shunt of pulmonary to systolic blood flow ratio
ASD closure has been established as an effective (Qp:Qs) of >1.5 were used to determine transcath-
© Author(s) (or their
treatment.3–6 Transcatheter closure can be safely eter ASD closure. We also confirmed no remark-
employer(s)) 2022. Re-­use
permitted under CC BY-­NC. No performed if PAH is mild or appears reversible able increase in PAP after balloon occlusion to test
commercial re-­use. See rights after shunt closure,7–9 while transcatheter closure is whether the patient tolerated transcatheter ASD
and permissions. Published contraindicated in severe PAH. The guidelines indi- closure.
by BMJ. cate that shunt closure can be performed in patients The primary endpoint was cardiovascular death
To cite: Takaya Y, Akagi T, with pulmonary vascular resistance (PVR) of ≤2.3 or hospitalisation due to heart failure or exacer-
Sakamoto I, et al. Heart Wood units, but shunt closure is not recommended bated PAH after transcatheter ASD closure. The
2022;108:382–387. in those with PVR of >4.6 Wood units.10–12 secondary endpoints were changes in mean PAP
382   Takaya Y, et al. Heart 2022;108:382–387. doi:10.1136/heartjnl-2021-319096
 Congenital heart disease
and PVR evaluated by cardiac catheterisation and estimated PAH-­specific medications because of no significant decrease in
systolic PAP evaluated by transthoracic echocardiography. PVR.
Changes in WHO functional class and plasma B-­type natriuretic Clinical characteristics of the 42 patients are shown in table 1.
peptide (BNP) levels were evaluated. The regimens of PAH-­ The age at the time of transcatheter ASD closure was 51±18
specific medications were assessed at the time of transcatheter years (range 17–80 years). The median maximal defect diameter
ASD closure and at the latest follow-­up after transcatheter ASD was 23 mm. At baseline prior to PAH-­specific medication, 24
closure. Patients were followed up until the first documentation (57%) patients were in WHO functional class III or IV. Qp:Qs
of death or the end of follow-­up. was 1.9±0.8 (range 0.9–3.9), and PVR and mean PAP were
6.9±3.2 Wood units (range 3.0–15.9 Wood units) and 45±15
Clinical assessments mm Hg (range 25–104 mm Hg). Estimated systolic PAP was
We collected data, such as age, sex, haemodynamic parameters, 78±26 mm Hg.
WHO functional class, BNP levels and transthoracic echocardio-
graphic parameters. Data collection was conducted at baseline PAH-specific medications
prior to PAH-­specific medications, at the time of transcatheter At the time of transcatheter ASD closure, 31 (74%) patients
ASD closure after PAH-­specific medications, and at the latest received a combination therapy with either two (n=13) or three
follow-­up after transcatheter ASD closure. Haemodynamic PAH-­ specific medications (n=18). The remaining 11 (26%)
parameters included PVR, mean PAP and Qp:Qs. Transthoracic patients received a single therapy. PAH-­ specific medications
echocardiography evaluated estimated systolic PAP, which was consisted of endothelin receptor antagonists (bosentan: n=11,
derived from right ventricular systolic pressure estimated using ambrisentan: n=8 and macitentan: n=15), phosphodiesterase
tricuspid regurgitation velocity (v) and the Bernoulli equation type-­5 inhibitors (sildenafil: n=13 and tadalafil: n=20), pros-
as 4 v2+right atrial pressure. Right atrial pressure was esti- tacyclins (beraprost: n=13, selexipag: n=6, epoprostenol: n=4
mated from the diameter of inferior vena cava and respiratory and treprostinil: n=2) and soluble guanylate cyclase stimulators
collapse.19 Adverse events, such as death and hospitalisation, (riociguat: n=1). Six patients were treated with intravenous
were investigated during the follow-­up period after transcatheter administration of epoprostenol or treprostinil. The median
ASD closure. The regimens of PAH-­specific medications were duration of PAH-­specific medications before transcatheter ASD
collected. closure was 9 months (range 1–87 months).
After PAH-­specific medications, Qp:Qs was 2.4±1.2 (range
Statistical analysis 1.2–6.3), which was increased, compared with that at baseline
Data are presented as mean±SD for continuous variables and (p=0.03). PVR and mean PAP were 4.0±1.5 Wood units (range
as number and percentage for categorical variables. Differences 1.5–7.1 Wood units) and 35±9 mm Hg (range 18–61 mm Hg),
were analysed using the Wilcoxon signed-­rank test for contin- which were decreased, compared with those at baseline (p<0.01
uous variables and the marginal homogeneity test for categorical and p<0.01).
variables. Event-­
free survival rate was estimated by Kaplan-­
Meier analysis. Statistical analysis was performed with JMP Transcatheter ASD closure
V.14.0 (SAS Institute, Cary, North Carolina, USA), and signifi- Transcatheter closure was performed using the Amplatzer Septal
cance was defined as a p value of <0.05. Occluder (Abbott, Chicago, Illinois, USA) with a median size of
25 mm in 31 patients, and using the Occlutech Figulla Flex Ⅱ
Patient and public involvement Occluder (Occlutech GmbH, Jena, Germany) with a median size
Participants were not involved in the design, conduct, reporting of 26 mm in 11 patients. There were no complications related to
or dissemination plans of our research. the procedure. No patients developed pulmonary hypertensive
crisis during the procedure.
RESULTS
Patient characteristics Clinical outcomes
Forty-­seven patients with ASD complicated with PAH received One patient who was 80 years old at the time of transcatheter
PAH-­specific medications in the 13 institutions. Of the 47 ASD closure died at 25 months after transcatheter closure. The
patients, 42 subsequently underwent transcatheter ASD closure. cause of death was unknown, but we included it as cardiovascular
Five patients abandoned shunt closure during treatment of death. One patient was hospitalised due to right heart failure at
14 months. During the median follow-­up period after transcath-
eter ASD closure of 33 months (range 1–126 months), the other
patients survived without any hospitalisations (figure 1).
Table 1 Clinical characteristics (n=42)
WHO functional class was improved at the latest follow-­up
Age at transcatheter ASD closure (years) 51±18 after transcatheter ASD closure, compared with that at baseline
Female 32 (76) (p<0.01). All the 24 patients with WHO functional class III or
Maximum defect diameter (mm) 23 IV at baseline had WHO functional class I or II at the latest
WHO functional class I or II 18 (43) follow-­up. No patients had deterioration (figure 2). Plasma BNP
WHO functional class III or IV 24 (57) levels were decreased at the latest follow-­up, compared with
B-­type natriuretic peptide (pg/mL) 158±192 those at baseline (158±192 to 85±86 pg/mL, p=0.03).
Pulmonary vascular resistance (Wood unit) 6.9±3.2
Mean PAP (mm Hg) 45±15 PAH after transcatheter ASD closure
Pulmonary to systemic blood flow ratio 1.9±0.8 Twenty-­six of the 42 patients had cardiac catheterisation
Estimated systolic PAP (mm Hg) 78±26 performed during the follow-­up period after transcatheter ASD
Data are presented as mean±SD, median or number (%) of patients. closure. Among these 26 patients, mean PAP was decreased,
ASD, atrial septal defect; PAP, pulmonary artery pressure. compared with that at the time of transcatheter ASD closure
Takaya Y, et al. Heart 2022;108:382–387. doi:10.1136/heartjnl-2021-319096 383
 Congenital heart disease

Figure 3 Mean PAP and PVR after transcatheter ASD closure. Mean
PAP was significantly decreased (p<0.01). PVR tended to be decreased
(p=0.08). ASD, atrial septal defect; PAP, pulmonary artery pressure; PVR,
pulmonary vascular resistance.
Figure 1 Event-­free survival rate. Survival rate without cardiovascular
death or hospitalisation due to heart failure or exacerbated pulmonary patients had a reduction from three medications to two medi-
arterial hypertension. cations, and two patients had a reduction from two medications
to one medication. The remaining three patients had discon-
(34±9 to 25±7 mm Hg, p<0.01) (figure 3). Mean PAP ranged tinuation of PAH-­ specific medications. These eight patients
from 12 to 42 mm Hg. Mean PAP of <25 mm Hg was observed had no PAH exacerbation. An increase in PAH-­specific medi-
in 13 (50%) of the 26 patients. PVR tended to be decreased, cations was observed in five (12%) patients. Three patients had
compared with that at the time of transcatheter ASD closure one medication added, and one patient had two medications
(4.1±1.6 to 3.2±1.7 Wood units, p=0.08). added. In one patient, the dose of PAH-­specific medication was
Estimated systolic PAP was obtained during the follow-­ up increased. These five patients had a Qp:Qs of 1.5±0.4, a PVR
period after transcatheter ASD closure in all the 42 patients. of 6.1±3.8 Wood units and a mean PAP of 50±15 mm Hg at
Estimated systolic PAP was decreased at the time of transcath- baseline. During the follow-­up period, PVR and mean PAP were
eter ASD closure, compared with that at baseline (78±26 to decreased to 2.5±1.2 Wood units and 25±6 mm Hg.
66±22 mm Hg, p=0.02). Further reduction was observed at the
follow-­up period (66±22 to 38±10 mm Hg, p<0.01) (figure 4). Severe PAH
Normalisation of estimated systolic PAP, which was defined as When severe PAH was defined as a mean PAP of ≥40 mm Hg
<40 mm Hg, was observed in 21 (50%) of the 42 patients. and a PVR of ≥5.0 Wood units with a Qp:Qs of <1.5, 14 of
the 42 patients had severe PAH at baseline. During the median
PAH-specific medications after transcatheter ASD closure follow-­up period of 37 months (range 8–110 months), all the
The regimens of PAH-­specific medications remained unchanged 14 patients survived without any hospitalisation. Among the
in 29 (69%) of the 42 patients. A reduction in PAH-­specific 11 patients who had cardiac catheterisation performed during
medications was observed in eight (19%) patients. Three the follow-­up period, the mean PAP and PVR were decreased,
compared with those at baseline (61±14 to 27±7 mm Hg,

Figure 4 Estimated systolic PAP. Estimated systolic PAP was

significantly decreased at the time of transcatheter ASD closure after
PAH-­specific medications, compared with that at baseline prior to
Figure 2 WHO functional class. WHO functional class at baseline PAH-­specific medications (p=0.02). Estimated systolic PAP was further
prior to pulmonary arterial hypertension-­specific medications and at decreased at the follow-­up after transcatheter ASD closure (p<0.01).
the follow-­up after transcatheter atrial septal defect closure. WHO ASD, atrial septal defect; PAH, pulmonary arterial hypertension; PAP,
functional class was significantly improved (p<0.01). pulmonary artery pressure.
384 Takaya Y, et al. Heart 2022;108:382–387. doi:10.1136/heartjnl-2021-319096
 Congenital heart disease
p<0.01; 9.7±3.2 to 3.6±1.6 Wood units, p<0.01). No patients transcatheter closure and as the goal of PAH-­specific medica-
had an increase in PAH-­specific medications. tions before transcatheter closure. Additionally, with regard
to PVR at the time of diagnosis before starting PAH-­specific
medications, the present study included patients with high PVR
DISCUSSION values, but transcatheter ASD closure was performed following
ASD complicated with PAH PAH-­specific medications, such as combination therapy. An ASD
ASD is often complicated by PAH.1 Previous studies reported which is previously considered unrepairable due to severe PAH
that shunt closure did not always improve PAH.20 21 Patients can become a candidate for transcatheter closure if the patient
who developed PAH after shunt closure had a worse prog- responds to PAH-­specific medications. Our study suggests that
nosis compared with those treated with medical therapy.22 23 the treat-­and-­repair strategy should be applied, regardless of the
Therefore, ASD closure has been considered to be unsuitable in value of PVR at the time of diagnosis. Aggressive treatment for
patients with PAH. The European Society of Cardiology guide- PAH is important to extend the indication of transcatheter ASD
line indicates a PVR of <5.0 Wood units as the upper limit for closure.
operability in patients with ASD.24 In several guidelines, shunt However, once Eisenmenger syndrome develops, ASD closure
closure is not recommended in patients with a PVR of >4.6 is contraindicated. This is because shunt closure may sacrifice
Wood units.10–12 However, data are limited in patients compli- the right-­sided pressure relief role, leading to worsening right
cated with PAH, especially those with severe PAH. heart failure. In patients with Eisenmenger syndrome, medical
In recent years, PAH-­ specific medications have advanced. management with PAH-­specific medications becomes the focus.
Furthermore, effective usage of PAH-­specific medications, such Our study did not include patients with ASD causing Eisen-
as combination therapy, has been demonstrated.25 Addition- menger syndrome.
ally, transcatheter closure, which is less invasive and has fewer
complications, has been performed. Because treatments for ASD
PAH-specific medications
and PAH are remarkably developing, the therapeutic strategy
After transcatheter ASD closure, the optimal regimens of PAH-­
for ASD complicated with PAH needs to be modified. A few
specific medications remain unknown. The present study showed
studies have reported the benefits of PAH-­specific medications
that PAH-­specific medications were largely unchanged during
and subsequent transcatheter closure (treat-­and-­repair strategy)
the follow-­up period. In patients with PAH, pulmonary vascular
in patients with ASD complicated with PAH,15–17 but the number
histopathology is changed by intimal proliferation and progres-
of patients was small. One study reported the data of 19 patients
sive distortion. The development of PAH after shunt closure is
who underwent ASD repair following PAH-­specific medications,
related to a poor prognosis.22 23 Maintaining low PAP contributes
but these included surgical closure.26
to an improvement in prognosis.25 Additionally, PAH is associ-
The present study showed that patients with ASD complicated
ated with ASD, but PAH is not caused by only increased blood
with PAH who underwent the treat-­and-­repair strategy had low
flow to the lungs.29 Therefore, it seems necessary to continue
complication and mortality rates. Most patients survived without
PAH-­specific medications even after the ASD is closed in patients
hospitalisation due to heart failure or exacerbated PAH. Addi-
with severe PAH. The regimens of PAH-­specific medications
tionally, WHO functional class was improved after transcatheter
should be carefully determined in individual patients. Further
ASD closure. PAP was significantly decreased after transcatheter
studies are required to clarify the appropriate regimens of PAH-­
ASD closure. One 80-­year-­old patient died, but transcatheter
specific medications.
ASD closure might not be suitable for this patient because of old
age. To the best of our knowledge, this is the first study to show
the efficacy of the treat-­and-­repair strategy for ASD complicated Clinical implication
with PAH in a large population. Unlike previous studies,27 28 Prognosis is worse in unclosed patients with ASD with PAH,30
transcatheter ASD closure was performed using non-­fenestrated whereas ASD closure is reported to be a risk for mortality in
devices in all the patients with PAH. Our study population was patients with PAH.2 30 Therefore, the appropriate therapeutic
in relatively good condition with predominantly left-­ to-­
right strategies for ASD with PAH, especially severe PAH, remain
shunt at baseline prior to PAH-­specific medications. Transcath- controversial.7–9 22 23 Physicians are confused about how treat
eter ASD closure using non-­fenestrated devices can be effective ASD with PAH because of the lack of evidence. The present
in this population. study showed low complication and mortality rates after PAH-­
The further reduction in PAP after transcatheter ASD closure specific medications and subsequent transcatheter closure. The
was considered to contribute to the clinical outcomes in our present study indicates that the treat-­and-­repair strategy has the
study. In patients with PAH, an adequate decrease in PAP plays potential to improve clinical outcomes in patients with ASD
an important role in improving prognosis. One study showed complicated with PAH.
that patients with PAH with mean PAP of <42.5 mm Hg by
aggressive treatment of PAH-­specific medications survived for a Study limitations
long time.25 In the present study, all the 26 patients who repeated First, this was a retrospective study. There was no control
cardiac catheterisation during the follow-­up period had a mean group. In this study, we involved the institutions where the
PAP of <42.5 mm Hg, including 13 patients with a mean PAP of patients were referred for consideration of transcatheter closure
<25 mm Hg. This value of mean PAP may be useful as an indi- of ASD complicated with PAH, and enrolled patients who
cator for managing PAH-­specific medications after transcatheter responded to PAH-­specific medications and underwent tran-
closure. scatheter closure. The study population was likely a less sick
The upper limits of PVR for transcatheter ASD closure after cohort. We did not investigate the entire ASD with PAH popu-
PAH-­specific medications remain unclear. In the present study, lation, including Eisenmenger syndrome. Therefore, this study
the majority of patients had a PVR of ≤5.0 Wood units at the time showed the results of the treat-­and-­repair strategy in selected
of transcatheter ASD closure. This result suggests that a PVR of patients with a favourable response to PAH-­specific medica-
≤5.0 Wood units is appropriate as the criterion for performing tions. Furthermore, clinical outcomes in patients who did not
Takaya Y, et al. Heart 2022;108:382–387. doi:10.1136/heartjnl-2021-319096 385
 Congenital heart disease
respond to PAH-­specific medications and did not get transcath- Contributors All authors contributed to the collection of data, discussion and
eter closure were not assessed. It was uncertain whether tran- interpretation of the data, and the writing of the report. All authors reviewed and
approved the manuscript for submission. The study was designed by YT, TA, KN and
scatheter ASD closure led to the clinical outcomes, including the HI. The analysis was performed by YT. The manuscript was written by YT.
reduction in PAP. The indication for ASD closure could not be
Funding The authors have not declared a specific grant for this research from any
clarified. Second, this was a relatively large-­scale study for eval- funding agency in the public, commercial or not-­for-­profit sectors.
uating the effect of the treat-­and-­repair strategy, but the number
Competing interests None declared.
of patients was small. Third, the follow-­up period after tran-
Patient and public involvement Patients and/or the public were not involved in
scatheter ASD closure was not long. Fourth, this study did not
the design, or conduct, or reporting, or dissemination plans of this research.
include patients who underwent surgical closure. Transcatheter
Patient consent for publication Not required.
closure has become an alternative to surgical closure. Therefore,
this study evaluated the effect of PAH-­specific medications and Ethics approval This study was in accordance with the Declaration of Helsinki and
approved by the ethical committee of our institution. Informed consent was obtained
subsequent transcatheter closure. Finally, the regimens of PAH-­ before entering this study.
specific medications were not uniform because these treatments
Provenance and peer review Not commissioned; externally peer reviewed.
were introduced by individual cardiologists. The decision to
undergo transcatheter ASD closure was based on judgement by Data availability statement This study is based on data from our institutions.
The data are available from the corresponding author on reasonable request.
cardiologists.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
CONCLUSIONS and license their derivative works on different terms, provided the original work is
This multicentre, relatively large-­scale observational study shows properly cited, appropriate credit is given, any changes made indicated, and the use
low complication and mortality rates with a reduction in PAP is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
after PAH-­ specific medications and subsequent transcatheter
ORCID iD
ASD closure. Our findings suggest that the treat-­ and-­
repair Yoichi Takaya http://orcid.org/0000-0003-4872-8669
strategy may be a reasonable therapeutic option in selected
patients with ASD complicated with PAH who have a favourable
response of medical therapy. REFERENCES
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