G Model

JJCC-1498; No. of Pages 7

Journal of Cardiology xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Journal of Cardiology
journal homepage: www.elsevier.com/locate/jjcc

Original article

Intergenerational differences in the effects of transcatheter closure of

atrial septal defects on cardiac function
Hideki Tashiro (MD, PhD)a,*, Kenji Suda (MD, PhD, FJCC)b, Motofumi Iemura (MD, PhD)c,
Youzou Teramachi (MD)c
a
Division of Cardiology, St. Mary’s Hospital, Kurume, Japan
b
Department of Pediatrics, Kurume University, Kurume, Japan
c
Division of Pediatric Cardiology, St. Mary’s Hospital, Kurume, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Background: Little is known regarding intergenerational differences in the effects of atrial sepal defect
Received 13 August 2016 (ASD) closure on the left heart. We therefore analyzed age-related serial changes in the left heart
Received in revised form 14 March 2017 following ASD closure.
Accepted 19 March 2017
Methods: We studied 50 patients with an isolated ASD who underwent successful transcatheter closure
Available online xxx
using Amplatzer septal occluders (St. Jude Medical, Little Canada, MN, USA) between June 2007 and June
2013. Patients were divided into three age groups: young patients aged 17 years; middle-aged patients
Keywords:
aged 18–50 years; and older patients aged >50 years. Multi-modal echocardiographic studies with
Congenital heart disease
different views were performed before and at 1 day, 1–3 months, and 6–12 months after ASD closure.
Transcatheter closure of atrial sepal defect
Diastolic dysfunction Echocardiographic variables were compared among the groups at different time points after closure.
Echocardiography Results: Left ventricular end-diastolic and end-systolic volume indices (EDVI and ESVI) in the older
group were significantly smaller than those in the other groups before closure. EDVI and ESVI increased
with time after closure in all groups with stable ejection fractions. However, EDVI and ESVI remained
significantly smaller in the older group compared with the other groups. There was a significant
interaction among the age groups only in terms of left atrial volume index (LAVI). LAVI increased
significantly with time in the older group, but did not change in the other groups.
Conclusion: Although the left ventricle enlarged with time after ASD closure in all age groups, left
ventricular size in older patients never reached that in younger patients. In addition to this inadequate
enlargement of the left ventricle, diastolic dysfunction might also result in late left atrial enlargement in
older patients following ASD closure.
ß 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Secundum-type atrial septal defect (ASD) is a common form of
congenital heart disease [1]. Transcatheter closure has been
established as an alternative treatment to surgical closure for
isolated secundum-type ASD [2,3], and several studies have
described transcatheter closure as a safe and minimally invasive
therapy for ASD [4,5]. Although transcatheter repair is associated
with low risk and can be definite in older patients [6], differences
among generations in terms of left-heart responses to disappear-
ance of the left-to-right shunt following ASD closure remain
unclear. We therefore analyzed serial echocardiographic changes
in the left heart in different generations to compare the age-related
* Corresponding author at: Division of Cardiology, St. Mary’s Hospital,
422 Tubuku-honmachi, Kurume 830-8543, Japan.
E-mail address: tashiro@st-mary-med.or.jp (H. Tashiro).
chronic effects of ASD closure on left ventricular (LV) diastolic and
systolic volumes and functions.
Methods
We retrospectively studied 50 patients with an isolated ASD
who underwent successful transcatheter closure at St. Mary’s
Hospital between June 2007 and June 2013, and for whom
sufficient data were available. This study complied with the
Declaration of Helsinki. ASD closure was performed using
Amplatzer septal occluders (St. Jude Medical, Little Canada, MN,
USA) in all patients. All patients were in sinus rhythm at the time of
echocardiography and without ischemic heart disease at ASD
closure. The definitions of hypertension were based on the
Japanese Society of Hypertension Guidelines for the Management
of Hypertension 2014. Development of heart failure was diagnosed

http://dx.doi.org/10.1016/j.jjcc.2017.03.014
0914-5087/ß 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Tashiro H, et al. Intergenerational differences in the effects of transcatheter closure of atrial septal
defects on cardiac function. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2017.03.014
G Model
JJCC-1498; No. of Pages 7

2 H. Tashiro et al. / Journal of Cardiology xxx (2017) xxx–xxx

by apparent heart failure symptoms, cardiomegaly, or effusion on
chest X-ray, and laboratory data. In this retrospective analysis, the
patients were divided into three groups according to their age: a
young group 17 years (n = 17, 6 males); a middle-aged group
aged 18–50 years (n = 19 patients, 4 males); and an older group
aged >50 years (n = 14 patients, 3 males).
All patients underwent multi-modal echocardiography before
and 1 day, 1–3 months, and 6–12 months after ASD closure.
Echocardiographic images, including 2-dimensional and Doppler
studies, were obtained using a Vivid 7 (General Electric Company,
Fairfield, CT, USA) with standard parasternal and apical views.
LV end-diastolic and end-systolic volumes were measured in
conventional 2-dimensional echocardiography using the biplane-
modified Simpson’s method, and the ejection fraction (EF) was
calculated. Cardiac output was calculated as follows: (LV end-
diastolic volume  end-systolic volume)  heart rate. Left atrial
(LA) volume was determined by the biplane area–length method.
Right atrial (RA) area was estimated by planimetry at the end of
ventricular systole in the apical 4-chamber view [7]. All these
values were measured using the EchoPac PC (General Electric
Company) and indexed to body surface area.
Transmitral inflow velocity was recorded from conventional
pulsed wave Doppler in the apical view. Deceleration time, peak
velocity of early diastolic inflow (E), and peak flow velocity of late
diastolic inflow (A) were measured [8] and the E/A ratio was
calculated.
In tissue Doppler imaging, the sampling volume was placed at
the basal lateral wall in the apical 4-chamber view [8,9] and peak
early diastolic mitral annular velocity (e0 ) was recorded.
LV mass before ASD closure was calculated in B-mode using the
area–length method [10] according to American Society of
Echocardiography recommendations, and indexed to body surface
area. The ratio of LV mass divided by end-diastolic volume was
determined for each patient.
Demographic variables at ASD closure, including height and
weight, and comorbidities, such as diabetes, hypertension, and
paroxysmal atrial fibrillation, were determined. Hemodynamic
variables, including mean pulmonary artery pressure, systolic and
diastolic aortic pressures, mean LA pressure, pulmonary-to-
systemic flow ratio, and pulmonary vascular resistance were
measured by cardiac catheterization. Transesophageal echocardi-
ography was performed at ASD closure and the device sizes were
determined. The defect widths on the major and minor axes were
measured. The area of the defect was calculated by assuming its
shape to be an ideal ellipse and using the formula: area of the
defect = pab/4, where a is width on the major axis and b is width on
the minor axis [11]. ASD area and device size were indexed to body
surface area.
All variables are expressed as the mean  standard deviation.
Data before ASD closure were compared with data 1 day, 1–3 months,
and 6–12 months after closure by repeated analysis of variance
(ANOVA). Post hoc comparisons were analyzed by Tukey’s test.
Causes of changes in LA volume and end-diastolic volume index
(EDVI) before and at 6–12 months after ASD closure were analyzed by
stepwise multiple regression analysis. Data were analyzed using the
JMP software package for Windows (version 8, SAS institute, Cary, NC,
USA). A value of p < 0.05 was considered to be significant.
Results
The patients’ backgrounds are shown in Table 1. As expected,
body height and body surface area were significantly lower in the
young group compared with the other groups (p < 0.001). Body
weight was significantly lower in the young group compared with
the middle-aged group (p = 0.001) (Table 1). Mean pulmonary
artery pressure was significantly lower in the middle-aged group
(p = 0.012) and LA pressure was significantly higher in the young
group compared with the older group (p = 0.012) (Table 1). The
incidences of hypertension (p = 0.019) and paroxysmal atrial
fibrillation (p < 0.001) were significantly higher in the older group
compared with the other groups (Table 1).
Echocardiographic and Doppler indices before ASD closure are
shown in Table 2. Before ASD closure, EDVI (p < 0.001) and end-
systolic volume index (ESVI) (p = 0.004) were significantly smaller,
but left atrial volume index (LAVI) (p < 0.001) was significantly
larger in the older group compared with the other groups. Cardiac
index was lower in the older group than in the other groups
(p < 0.001). The E/A ratio (p < 0.001) and e0 (p < 0.001) were
significantly lower but E/e0 was significantly higher in the older
group compared with the other groups (p = 0.008), and the
deceleration time was significantly longer in the older group
compared with the young group (p = 0.014). There was no
significant difference in LV mass index among the groups
(p = 0.129), but the LV mass divided by end-diastolic volume

Table 1
Patient characteristics.

Young group Middle-aged group Older group p-value

Number of patients 17 19 14
Age (years) 11.9  3.1*,# 28.3  8.0# 63  9 <0.001
Mean PA (mmHg) 15  3 13  3# 16  4 0.012
Systolic Ao (mmHg) 92  15 91  12 97  26 0.590
Diastolic Ao (mmHg) 51  7 53  9 50  12 0.666
Mean LA (mmHg) 9  3# 73 72 0.012
Qp/Qs 2.2  1.0 2.3  1.0 2.7  1.0 0.379
Shunt Ratio (%) 49.2  18.4 50.5  18.8 52.9  23.9 0.860
PVRI (dyne sec cm5 m–2) 59.8  32.6 47.1  18.8 70.4  35.6 0.082
Device size index (mm/m2) 14.1  4.7* 11.1  3.6 14.1  3.5* 0.037
Height (cm) 143.5  18.3* #
162.0  7.5 156.0  6.9 <0.001
Weight (kg) 40.6  18.2* 57.8  8.9 51.9  9.8 0.001
BSA (kg/m2) 1.2  0.3* # 1.6  0.2 1.5  0.2 <0.001
Heart Failure 0% 0% 7% 0.270
Hypertension 0%# 5%# 29% 0.019
Diabetic Mellitus 0% 5% 14% 0.185
Paroxysmal Atrial Fibrillation 0%# 0%# 36% <0.001

PA, pulmonary artery; Ao, aorta; LA, left atrium; Qp/Qs, pulmonary-to-systemic flow ratio; PVRI, pulmonary vascular resistance index; BSA, body surface area.
*
p < 0.05 vs middle-aged group.
#
p < 0.05 vs. older group.

Please cite this article in press as: Tashiro H, et al. Intergenerational differences in the effects of transcatheter closure of atrial septal
defects on cardiac function. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2017.03.014
G Model
JJCC-1498; No. of Pages 7

H. Tashiro et al. / Journal of Cardiology xxx (2017) xxx–xxx 3

Table 2
Echocardiographic and Doppler indices before ASD closure.

Young group Middle-aged group Older group p-value

# #
E/A 2.5  1.0 2.0  0.5 0.98  0.3 <0.001
Deceleration time (ms) 179.2  28.3*,# 206.4  35.7 211.9  33 0.014
e0 (m/s) 0.22  0.02* # 0.19  0.03# 0.11  0.03 <0.001
E/e0 4.5  0.8# 4.3  0.8# 5.5  1.5 0.008
EDVI (ml/m2) 47.1  11.2# 47.7  9.1# 35.4  7.7 <0.001
ESVI (ml/m2) 15.8  4.6# 15.1  4.1# 10.8  3.5 0.004
CI (ml/min/m2) 2238  620# 2138  476# 1553  329 <0.001
LAVI (ml/m2) 31.3  5.9# 29.2  8.0# 43.2  13.6 <0.001
ASD area index (mm2/m2) 96.7  51.1# 77.2  32.6# 141.7  67.8 0.001
RA area index (cm2/m2) 14.9  2.4 12.7  2.3# 16.1  4.2 0.005
EF (%) 68.1  6.4 68.2  5.6 69.1  7.2 0.891
LV mass index (g/m2) 67.4  12.4 70.4  12.6 78.8  20.8 0.129
LV mass/EDV (g/ml) 1.5  0.4# 1.5  0.2# 2.3  0.4 <0.001

ASD, atrial septal defect; E, early mitral inflow; A, late mitral inflow; e0 , peak early diastolic mitral annular velocity; HR, heart rate; EDVI, end-diastolic volume index; ESVI,
end-systolic volume index; CI, cardiac index; LAVI, left atrial volume index; RA, right atrial; EF, ejection fraction; LV, left ventricular.
*
p < 0.05 vs middle-aged group.
#
p < 0.05 vs. older group.

was significantly higher in the older group than in the other groups
(p < 0.001) (Table 2). ASD area index in the older group (p = 0.001)
was larger than in the other groups, and right atrial area index
(p = 0.005) was larger in the older group compared with the
middle-aged group (Table 2).
Most echocardiographic variables changed significantly
after ASD closure in all patients, except for LVEF and E/A
(Tables 3 and 4). Deceleration time increased 1 day after closure
(p = 0.007), while E/e0 (p < 0.001), EDVI (p < 0.001), ESVI
(p = 0.014), and LAVI (p < 0.001) increased and e0 decreased
(p < 0.001) with time after ASD closure (Tables 3 and 4).
However, the timing and magnitude of the significant changes
differed among echocardiographic variables depending on the
age groups, according to post hoc analysis. EDVI and ESVI
increased significantly after ASD closure in all age groups, but
LVEF did not change (Table 4).
ANOVA showed a significant interaction among age groups only in
terms of LAVI (p < 0.05) (Fig. 1, Table 4). Only LAVI increased
significantly after ASD closure in the older group according to post
hoc analysis (p < 0.05). LAVI at 6–12 months after ASD closure was
significantly correlated with E/A (p = 0.028), e0 (p < 0.001), E/e0
(p < 0.001), ASD area index (p < 0.001), and LV mass index
(p = 0.032) before ASD closure (Fig. 2), but not with EDVI, EF, RA
area index, or deceleration time before ASD closure (Fig. 2). Device

Table 3
Time courses of Doppler indices before and after ASD closure.

Young group Middle-aged group Older group Total p-value (group) Interaction

E/A 0.665
Before 2.5  1.0 2.0  0.5 1.0  0.3 1.9  0.9
One day 2.5  0.6 1.8  0.4 1.0  0.3 1.8  0.7
1–3 months 2.2  0.6 1.9  0.6 1.1  0.4 1.8  0.7 <0.001
6–12 months 2.5  0.8 2.0  0.7 1.2  0.5 1.9  0.8
p-value (time) 0.395
DCT (ms) 0.218
Before 179.2  28.3 206.4  35.7 211.9  33.0 198.7  34.9
One day 201.3  33.8 234.8  36.8 233.9  46.4 223.2  41.1*
1–3 months 175.8  36.7 231.9  42.4 240.6  71.9 215.0  57.4 <0.001
6–12 months 197.6  32.8 213.3  43.7 235  40.7 214.0  41.4
p-value (time) 0.007
e0 (cm/s) 0.829
Before 0.22  0.02 0.19  0.03 0.11  0.03 0.18  0.05
One day 0.20  0.04* 0.16  0.03* 0.09  0.02 0.15  0.05*
1–3 months 0.20  0.04 0.17  0.03 0.10  0.02 0.16  0.05* <0.001
6–12 months 0.19  0.03* 0.17  0.04 0.10  0.02 0.16  0.05*
p-value (time) <0.001
E/e’ 0.443
Before 4.5  0.8 4.3  0.8 5.5  1.5 4.7  1.1
One day 5.0  1.3 4.8  1.3 7.2  3.5 5.5  2.3*
1–3 months 5.3  1.3 4.8  1.2 7.1  2.8 5.6  2.0* <0.001
6–12 months 5.4  1.2 5.2  1.7 7.8  3.4* 6.0  2.4*
p-value (time) <0.001
HR (beats/min) 0.395
Before 71.9  12.6 65.9  9.0 64.5  9.5 67.6  10.9
One day 72.9  12.2 69.0  11.9 69.9  13.7 70.6  12.4
1–3 months 71.9  12.8 64.5  10.8 63.0  7.2 66.6  11.1# 0.115
6–12 months 66.9  12.2 60.4  6.0# 64.7  11.2 63.8  10.2#
p-value (time) 0.003

ASD, atrial septal defect; E, early mitral inflow; A, late mitral inflow; DCT, deceleration time; e0 , peak early diastolic mitral annular velocity; HR, heart rate.
*
p < 0.05 vs. before ASD closure.
#
p < 0.05 vs. 1 day after ASD closure.

Please cite this article in press as: Tashiro H, et al. Intergenerational differences in the effects of transcatheter closure of atrial septal
defects on cardiac function. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2017.03.014
G Model
JJCC-1498; No. of Pages 7

4 H. Tashiro et al. / Journal of Cardiology xxx (2017) xxx–xxx

Table 4
Time courses of echocardiographic indices before and after ASD closure.

Young group Middle-aged group Older group Total p-value (group) Interaction
2
EDVI (ml/m ) 0.548
Before 47.1  11.2 47.7  9.1 35.4  7.7 44.0  10.9
One day 51.4  11.5 52.2  11.3 40.6  9.5 48.7  11.8*
1–3 months 58.4  12.3* 54.9  10.1* 46.6  9.6* 53.7  11.5* 0.006
6–12 months 58.6  13.6* 58.2  11.9* 48.7  12.2* 55.7  13.1*
p-value (time) <0.001
ESVI (ml/m2) 0.314
Before 15.8  4.6 15.1  4.1 10.8  3.5 14.1  4.5
One day 16.9  4.4 18.6  5.2* 13.3  5.1 16.6  4.5*
1–3 months 18.4  4.7* 17.4  5.0 14.5  4.7* 16.9  5.1* <0.001
6–12 months 18.3  4.5 19.9  6.3* 15.4  6.2* 18.1  5.9*
p-value (time) 0.014
LAVI (ml/m2) <0.001
Before 31.3  5.9 29.2  8.0 43.2  13.6 33.8  10.9
One day 31  5.9 30  7.6 44.1  15.2 34.3  11.6
1–3 months 33.4  9.2 31.1  7.7 52.1  14.7* 37.7  13.8* <0.001
6–12 months 33.9  8.8 32.1  9.5 56.7  22* 39.6  17.4*
p-value (time) <0.001
EF (%) 0.755
Before 68.1  6.4 68.2  5.6 69.1  7.2 68.5  6.2
One day 67.8  5.0 64.6  6.9 67.6  6.7 66.6  6.3
1–3 months 68.4  5.0 68.6  8.2 68.9  7.4 68.6  6.9 0.278
6–12 months 68.6  5.5 65.8  6.5 68.9  7.0 67.6  6.4
p-value (time) 0.461
CI 0.220
Before 2238  620 2138  476 1553  329 2008  567
One day 2496  619 2268  453 1867  361 2233  546*
1–3 months 2855  821 2370  436* 2000  404 2432  671* <0.001
6–12 months 2663  714 2304  505 2149  653* 2383  647*
p-value (time) <0.001

ASD, atrial septal defect; EDVI, end-diastolic volume index; ESVI, end-systolic volume index; LAVI, left atrial volume index; EF, ejection fraction; CI, cardiac index.
*
p < 0.05 vs. before ASD closure.

size index was significantly correlated with LAVI at 6–12 months
(Fig. 2).
There was no difference in changes in LAVI, EDVI, ESVI, e0 , or E/e0
between older patients with and without atrial fibrillation
(Table 5), although LAVI, EDVI, and E/e0 were significantly
increased by the presence of hypertension in the older group
(Table 5).
We examined the relationships between LAVI before ASD
closure and age, sex, e0 , E/e0 , LV mass index, EF, pulmonary-to-
systemic flow ratio, pulmonary vascular resistance index, ASD area
index, and RA area index before ASD closure. Stepwise multiple
regression analysis identified age and E/e0 as significant factors
correlated with LAVI before ASD closure (Table 6). We also
examined the relationships between LAVI at 6–12 months after
ASD closure and the above factors, and device size index. Stepwise
multiple regression analysis identified age, E/e0 , and ASD area index
before ASD closure as significant factors correlated with LAVI at 6–
12 months after closure (Table 6), with age showing the highest
standardized partial regression coefficient and E/e0 second highest.
We performed the same analysis for EDVI before ASD closure and
EDVI at 6–12 months after ASD closure. Stepwise multiple
regression analysis identified age and sex as significant factors
correlated with EDVI before ASD closure (Table 6) and age and LV
mass index as significant factors correlated with EDVI at 6–12
months after ASD closure (Table 6).

Discussion

The results of this study showed that elimination of shunt flow

Fig. 1. Time course of LAVI before and after ASD closure. Graph showing no
significant increase in LAVI in the young and middle-aged groups, but significant
increase inthe older group (before vs. 1–3 months and 6–12 months after the
procedure). Vertical axis indicates LAVI and horizontal axis shows the time course.
LAVI, left atrial volume index; ASD, atrial septal defect.
from ASD induced specific changes in LV volume and function.
These changes generally showed similar trends, regardless of age,
but the timing and the magnitude of the changes differed among
generations, with the difference in LAVI being especially pro-
nounced.
Doppler indices concerning diastolic function were poorest in
older patients, and even though all Doppler indices changed in the
same direction with time after ASD closure in all age groups, the
age-dependent differences persisted. In our previous study, we
showed that deceleration time, e0 , and E/e0 were worse at 1 day
after ASD closure [12]. In the current study, however, deceleration
time increased 1 day after ASD closure, e0 decreased, and E/e0
increased significantly over time but E/A did not change. There
were no significant interactions among the groups according to
ANOVA. Although congestive heart failure is a complication of

Please cite this article in press as: Tashiro H, et al. Intergenerational differences in the effects of transcatheter closure of atrial septal
defects on cardiac function. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2017.03.014
G Model
JJCC-1498; No. of Pages 7
H. Tashiro et al. / Journal of Cardiology xxx (2017) xxx–xxx
Fig. 2. Correlations between echocardiographic and clinical parameters and LAVI at
6–12 months after ASD closure. Graphs showing relationships between LAVI at 6–
12 months after closure and E/e0 , e0 , DCT, E/A, LV mass index, device size index, EF,
EDVI, ASD area index, and RA area index. Vertical axes indicate LAVI and horizontal
axes show each index.
E, early mitral inflow; e0 , peak early diastolic mitral annular velocity; DCT,
deceleration time; LAVI, left atrial volume index; EDVI, end-diastolic ventricular
volume index; EF, ejection fraction; LV, left ventricle; RA, right atrium; ASD, atrial
septal defect.
catheter ASD occlusion [13,14], it usually occurs in older patients
during the early phase. No patients in the older group in the current
study developed clinically apparent congestive heart failure, but
two showed a small amount of pleural effusion on chest X-rays
Please cite this article in press as: Tashiro H, et al. Intergenerational differences in the effects of transcatheter closure of atrial septal
defects on cardiac function. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2017.03.014
5
1 day after ASD closure, and showed an E/e0 > 10 on echocardiog-
raphy. According to our results, adaptation of diastolic dysfunction
was similar in all three groups, but basic diastolic function was
poor among older patients.
Kahn et al. reported that ASD closure in older patients was safe
and effective, and also resulted in symptomatic relief by improving
functional class with favorable cardiac remodeling [14]. Takaya
et al. showed that exercise capacity could be improved over the
long term after transcatheter closure of ASD in older patients [15].
These reports suggest that older patients adapt to hemodynamic
changes after ASD closure. In the current study, LV volume and EF
were measured sequentially, and diastolic and systolic LV volume
increased while EF did not change in any of the groups. These
results were in agreement with those of previous studies [14,16],
including our own, which reported that LV size was increased 1 day
after ASD closure [12]. Following device closure, the left-to-right
shunt was abolished and LV filling improved, resulting in an
increase in LV dimension. Although EF does not change, cardiac
index increased because of the increasing LV dimension induced by
an increase in inflow volume after disappearance of the shunt.
Interestingly, LV remodeling differed among the groups. LV was
smallest in older patients with ASD. LV size increased with time
after ASD closure in all the groups and finally normalized in the
young and the middle-aged groups; however, LV size in the older
group never reached that in the other groups. Indeed, multiple
regression analysis showed that EDVI before and at 6–12 months
after ASD closure were significantly correlated with age. LV
compliance may represent one mechanism responsible for the
observed age-dependent difference in LV remodeling after ASD
closure. LV compliance was lowest in the older group, as indicated
by a higher LV mass-to-volume ratio, suggesting that the LV
volume may not increase sufficiently in this age group.
The significant intergenerational difference was also reflected
by a specific increase in LAVI in the older group. According to our
results, LAVI increased significantly at 1–3 and 6–12 months after
ASD closure in the old group, but did not change in either of the
other groups. Previous studies have reported variable results
regarding changes in LA volume after ASD closure. Pascotto et al.
found that ASD closure did not affect LA volume [17], although
Salehian et al. showed that LA volume decreased after ASD closure
[16]. We found no change in LA volume in the young and middle-
aged groups, consistent with Pascotto et al.’s study in which the
subjects were young (22  18 years) and asymptomatic [17]. How-
ever, more than half the subjects in Salehian et al.’s study were in New
York Heart Association functional classification II or higher, but were
still younger than the patients in our older group (45.5  16.3 years
vs. 63.4  9.3 years) and older than our middle-aged group
(23.8  8.0 years) [16]. These differences in clinical condition and
age might explain the differences among studies in terms of LA
volume after ASD closure. Abolishment of the left-to-right atrium
shunt decreases LA inflow, but leads to increased LV filling and
increased LA afterload. These factors may therefore result in different
overall effects on LA volume. Indeed, although LAVI at 6–12 months
after ASD closure was not correlated with EF, EDVI, and deceleration
time, it was significantly correlated with E/A, e0 , E/e0 and LV mass
index, and multiple regression analysis identified age and E/e0 as
factors affecting LAVI before and at 6–12 months after ASD closure.
LAVI was larger in the older group than in the other groups at every
phase. Thus although diastolic dysfunction before ASD closure should
be related to LAVI in the older group (indicated by the significant
correlation with E/e0 ), that might deteriorate after ASD closure. This
age-specific change in LA volume might be associated with diastolic
dysfunction in older patients as a result of a thickened LV. Restricted
increase in LV volume and a high LV mass might lead to diastolic
dysfunction and increased LA volume. Cheng et al. showed that the LV
mass-to-volume ratio increased markedly with age, driven by a
G Model
JJCC-1498; No. of Pages 7

6 H. Tashiro et al. / Journal of Cardiology xxx (2017) xxx–xxx

Table 5
Impacts of paroxysmal atrial fibrillation and hypertension on echocardiographic data in older patients.

Af () n = 9 Af (+) n = 5 p-value Interaction HT() n = 10 HT(+) n = 4 p-value Interaction

2
LAVI (ml/m ) 0.805 0.066
Before 41.8  13.7 45.6  14.6 37.4  9.7 57.6  11.4
One day 42.8  17.3 46.4  12.1 38.6  12.2 57.8  14.4
1–3 months 49.6  13.8 56.6  16.6 0.666 49.6  14.8* 58.6  14.1 0.045
6–12 months 56.2  24.4* 57.7  16.6 50.0  14.4* 73.5  30.7*
Time <0.001 <0.001
EDVI (ml/m2) 0.929 0.154
Before 37.1  8.8 32.0  4.0 32.4  4.9 42.3  9.4
One day 41.7  11.2 38.5  5.7 36.7  6.0 50.3  10.3
1–3 months 47.8  10.2* 44.4  9.0* 0.425 44.6  10.3* 51.7  5.7 0.024
6–12 months 50.5  13.7* 45.4  9.1* 44.4  8.6* 59.5  14.1*
Time <0.001 <0.001
ESVI (ml/m2) 0.512 0.178
Before 11.8  3.9 9.1  1.7 9.7  2.2 13.6  4.9
One day 13.7  6.4 12.6  1.5 11.1  2.3 18.8  6.3
1–3 months 16.2  4.9 11.4  2.2 0.230 13.8  3.8 16.1  6.8 0.073
6–12 months 16.5  7.1* 13.5  4.5 14.3  4.9* 18.2  9.0
Time 0.005 0.005
e0 (m/s) 0.016 0.296
Before 0.10  0.02 0.13  0.03 0.11  0.03 0.11  0.02
One day 0.08  0.01 0.10  0.03 0.09  0.02 0.08  0.01
1–3 months 0.10  0.03 0.10  0.02 0.289 0.11  0.03 0.08  0.01 0.407
6–12 months 0.10  0.03 0.09  0.01* 0.10  0.02 0.10  0.01
Time 0.002 0.007
E/e0 0.965 0.230
Before 5.7  1.5 4.9  1.6 4.9  1.3 6.8  1.0
One day 7.6  3.8 6.5  3.1 6.9  3.9 8.0  2.4
1–3 months 7.2  3.2 7.0  2.0 0.621 5.8  1.1 10.3  3.2 0.018
6–12 months 7.9  3.9 7.4  2.3 6.6  2.6 10.6  3.7
Time 0.077 0.029

LAVI, left atrial volume index; Af, atrial fibrillation; HT, hypertension; EDVI, end-diastolic volume index; ESVI, end-systolic volume index; e0 , peak early diastolic mitral
annular velocity; E/, early mitral inflow.
*
p < 0.05 vs. before atrial septal defect closure.

substantial reduction in end-diastolic volume [18]. Furthermore, large devices might have affected LAVI. However, the ASD area
D’Andrea et al. showed an age-dependent LA volume increase index in the older group was also larger than in the other groups,
[19]. LAVI increased in older patients with and without hypertension which might have affected the results.
in the current study, and aging itself may thus have caused the LV This study had some limitations. Hypertension and paroxys-
thickening in older patients with ASD. mal atrial fibrillation might increase LA volume, and these
Device size and ASD defect area were significantly correlated comorbidities might thus have affected our results. Although
with LAVI in this study. Multiple regression analysis identified a paroxysmal atrial fibrillation did not affect LAVI, EDVI, ESVI, e0 ,
correlation between ASD area index and LAVI at 6–12 months after or E/e0 in the older group, hypertension increased LAVI, EDVI, and
ASD closure. It is possible that the relatively stiff, non-contractile, E/e0 in this age group. Because E/e0 correlates with mean atrial
pressure [20], hypertension might increase end-diastolic pres-
sure in the LV and expand the LA and LV. However, the interaction
Table 6 of LAVI in older patients with and without hypertension was not
Correlations between echocardiographic and clinical parameters and LAVI and EDVI
significant according to ANOVA. D’Andrea et al. reported that LA
before and at 6–12 months after ASD closure.
volume was significantly associated with age [19]. These results
p-value Standardized b suggest that age might be an important factor affecting LAVI,
LAVI before ASD closure regardless of the presence of hypertension or paroxysmal atrial
Age 0.025 0.30 fibrillation.
E/e0 0.014 0.32 We used 2-dimensional echocardiography, although 3-dimen-
ASD area index 0.115 0.20
sional echocardiography might have been more accurate. Howev-
LAVI at 6–12 months after ASD closure
Age 0.001 0.39 er, several studies have shown that LV and LA volumes determined
E/e0 0.002 0.36 by 2-dimensional echocardiography correlate well with the results
ASD area index 0.029 0.24 of 3-dimensional echocardiography [21].
EDVI before ASD closure The major limitations of this study were the grouping method
Age 0.001 0.40
Sex 0.002 0.37
and sample size. We divided patients arbitrarily into three groups
ASD area index 0.072 0.22 according to their age, and the results may have differed if more
EDVI at 6–12 months after ASD closure patients had been included and/or if the cut-off ages for the groups
Age 0.003 0.41 had been different. Notably, our results should be interpreted with
Sex 0.057 0.25
caution given that multiple regression analysis needs large sample
LV mass index 0.049 0.27
sizes. Furthermore, the retrospective, single-center nature of this
ASD, atrial septal defect; E, early mitral inflow; e0 , peak early diastolic mitral study did not allow us to examine the effect of grouping. However,
annular velocity; LAVI, left atrial volume index; EDVI, end diastolic volume
index; LV, left ventricle; b, partial regression coefficient.
we still demonstrated a significant intergenerational difference in
LA volume after ASD closure, which should remain significant if we

Please cite this article in press as: Tashiro H, et al. Intergenerational differences in the effects of transcatheter closure of atrial septal
defects on cardiac function. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2017.03.014
G Model
JJCC-1498; No. of Pages 7
H. Tashiro et al. / Journal of Cardiology xxx (2017) xxx–xxx
included even older patients. Further studies with larger sample
sizes are needed to verify these findings.
Our results may also have been affected by variations in the
timing of echocardiography. Because this study was retrospective,
echocardiograms were performed before and at 1 day, 1–3 months,
and 6–12 months after ASD closure. Most previous studies showed
significant remodeling of the heart within 6 months after ASD
closure [15–17]. The timing of the echocardiographic examina-
tions in this study should therefore reflect the general trends of
changes in LV volume and function. In this study, LAVI in the older
group was increased at the latest follow-up, but it was not clear if
LA volume continued to increase after this time, and further
follow-up data for a longer period of time are therefore needed to
determine the effects of ASD closure.
The LV shape is usually deformed in patients with ASD, and
measurements of volume might thus not be reliable. However,
Silverman et al. reported that the results of the biplane area–length
method correlated well with angiography in pediatric patients with
various congenital heart diseases [22]. Measurements of LA volume
in older patients are sometimes difficult. However, Heo et al.
reported that LA volume assessed from 2-dimensional echocardi-
ography was significantly correlated with measurements from
computed tomography in older patients, although 2-dimensional
echocardiography measurements were underestimates [23], sug-
gesting that the current measurements were reliable.
In conclusion, LV enlarges with time after ASD closure in
patients of all ages, but LV size in older patients does not reach that
of young or middle-aged patients. In addition to this inadequate
enlargement of the LV, diastolic dysfunction might also result in
late LA enlargement in older patients.
Funding
This research received no grant from any funding agency in the
public, commercial, or not-for-profit sectors.
Conflicts of interest
The authors declare that there is no conflict of interest.
References
[1] Dong L, Zhang F, Shu X, Guan L, Chen H. Left ventricular torsion in patients with
secundum atrial septal defect. Circ J 2009;73:1308–14.
[2] Du ZD, Hijazi ZM, Kleinman CS, Silverman NH, Larntz K. Comparison between
transcatheter and surgical of secundum atrial septal defect in children and
adults: results of multicenter nonrandomized trial. J Am Coll Cardiol
2009;39:1836–44.
[3] Akagi T. Current concept of transcatheter closure of atrial septal defect in
adults. J Cardiol 2015;65:17–25.
[4] Hoashi T, Yazaki S, Kagisaki K, Kitano M, Kubota SM, Shiraishi I, Ichikawa H.
Management of ostium secundum atrial septal defect in the era of percutane-
ous trans-catheter device closure: 7-year experience at a single institution. J
Cardiol 2015;65:418–22.
[5] Du ZD, Hijazi ZM, Kleinman CS, Silverman NH, Lantz K. Comparison between
transcatheter and surgical closure of secundum atrial defect in children and
adults: results of a multi center nonrandomized trial. J Am Coll Cardiol
2002;39:1836–44.
Please cite this article in press as: Tashiro H, et al. Intergenerational differences in the effects of transcatheter closure of atrial septal
defects on cardiac function. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2017.03.014
7
[6] Ewert P, Berger F, Nagdyman N, Kretschmar O, Dittrich S, Abdul-Khaliq H,
Lange P. Masked left ventricular restriction in elderly patients with atrial
septal defects: a contraindication for closure? Catheter Cardiovasc Interv
2001;52:177–80.
[7] Grünig E, Henn P, D’ Andrea A, Claussen M, Ehlken N, Maier F, Naeije R, Nagel C,
Prange F, Weidenhammer J, Fischer C, Bossone E. Reference values for and
determinants of right atrial area in healthy adults by two-dimensional echo-
cardiography. Circ Cardiovasc Imaging 2013;6:117–24.
[8] Kasner M, Westermann D, Steendijk P, Gaub R, Wilkenshoff U, Weitmann K,
Hoffmann W, Poller W, Schulthesis HP, Pauschinger M, Tschöpe C. Utility of
Doppler echocardiography and tissue Doppler imaging in the estimation of
diastolic function in heart failure with normal ejection fraction. A compara-
tive Doppler-conductance catheterization study. Circulation 2007;116:
637–47.
[9] McMahon CJ, Nagueh SF, Pignatelli RH, Denfield SW, Dreyer WJ, Price JF, Clunie
S, Bezold LI, Hays AL, Towbin JA, Eiden BW. Characterization of left ventricular
diastolic function by tissue Doppler imaging and clinical status in children
with hypertrophic cardiomyopathy. Circulation 2004;109:1756–62.
[10] Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA,
Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT,
Sutton MS, Stewart WJ. Recommendations for chamber quantification: a
report from the American Society of Echocardiography’s Guidelines and
standards committee and the chamber quantification writing group, devel-
oped in conjunction with the European Association of Echocardiography, a
branch of the European Society of Cardiology. J Am Soc Echocardiogr
2005;18:1440–63.
[11] Ishii M, Kato H, Inoue O, Takagi J, Maeno Y, Sugimura T, Miyake T, Kumate M,
Kosuga K, Ohishi K. Biplane transesophageal echo-Doppler studies of atrial
septal defects: quantitative evaluation and monitoring for transcatheter clo-
sure. Am Heart J 1993;125:1363–8.
[12] Tashiro H, Suda K, Tananari Y, Itou S. Impact of transcatheter closure of atrial
septal defects on cardiac function. J Med Ultrason 2012;39:147–53.
[13] Singhi AK, Mahesh K, Kumar RK. Pulmonary edema following transcatheter
closure of atrial septal defect. Ann Pediatr Cardiol 2010;3:90–1.
[14] Khan AA, Tan JL, Li W, Dimopoulos K, Spence MS, Chow P, Mullen MJ. The
impact of transcatheter atrial septal defect closure in the older population: a
prospective study. JACC Cardiovasc Interv 2010;3:276–81.
[15] Takaya Y, Taniguchi M, Akagi T, Nobusada S, Kusano K, Ito H, Sano S. Long-term
effects of transcatheter closure of atrial septal defect on cardiac remodeling
and exercise capacity in patients older than 40 years with a reduction in
cardiopulmonary function. J Interv Cardiol 2013;26:195–9.
[16] Salehian O, Horlick E, Schwerzmann M, Haberer K, McLaughlin P, Siu SC,
Webb G, Therrien J. Improvements in cardiac form and function after trans-
catheter closure of secundum atrial septal defects. J Am Coll Cardiol
2005;45:499–504.
[17] Pascotto M, Santoro G, Cerrato F, Caputo S, Bigazzi MC, Lacono C, Carrozza M,
Russo MG, Caianiello G, Calabrò R. Time-course of cardiac remodeling
following transcatheter closure of atrial septal defect. Int J Cardiol 2006;112:
348–52.
[18] Cheng S, Fernandes VRS, Bluemke DA, McClelland RL, Kronmal RA, Lima JAC.
Age-related left ventricular remodeling and associated risk for cardiovascular
outcomes. The multi-ethnic study of atherosclerosis. Circ Cardiovasc Imaging
2009;2:191–8.
[19] D’Andrea A, Riegler L, Rucco MA, Cocchia R, Scarafile R, Salerno G, Martone F,
Vriz O, Caso P, Calabrò R, Bossone E, Russo MG. Left atrial volume index in
healthy subjects: clinical and echocardiographic correlates. Echocardiography
2013;30:1001–7.
[20] Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ.
Clinical utility of Doppler echocardiography and tissue Doppler imaging in the
estimation of left ventricular filling pressures. A comparative simultaneous
Doppler-catheterization study. Circulation 2000;102:1788–94.
[21] Lang RM, Mor-Avi V, Sugeng L, Nieman PS, Sahn DJ. Three-dimensional
echocardiography: the benefits of the additional dimension. J Am Coll Cardiol
2006;48:2053–69.
[22] Silverman NH, Ports TA, Snider R, Schiller NB, Carlsson E, Heilbron DC.
Determination of left ventricular volume in children: echocardiographic
and angiographic comparisons. Circulation 1980;62:548–57.
[23] Heo R, Hong GR, Kim YJ, Mancina J, Cho IJ, Shim CY, Chang HJ, Ha JW, Chung N.
Automated quantification of left atrial size using three-beat averaging real-
time three dimensional echocardiography in patients with atrial fibrillation.
Cardiovasc Ultrasound 2015;13:38.