Association of the Clinical and Genetic Factors With Superior Vena Cava Arrhythmogenicity in Atrial Fibrillation

Abstract

Background:Atrial fibrillation (AF) can be initiated from arrhythmogenic foci within the muscular sleeves that extend not only into the pulmonary veins but also into both vena cavae. The superior vena cava (SVC) is a key target site for catheter ablation. Patients with SVC-derived AF often lack the clinical risk factors of AF.
Methods and Results:We conducted a meta-analysis of the clinical and genetic factors of 2,170 AF patients with and without SVC arrhythmogenicity. In agreement with previous reports, the left atrial diameter was smaller in AF patients with SVC arrhythmogenicity. Among 6 variants identified in a previous genome-wide association study in Japanese patients, rs2634073 and rs6584555 were associated with SVC arrhythmogenicity. This finding was confirmed in our meta-analysis using independent cohorts. We also found that SVC arrhythmogenicity was conditionally dependent on age, body mass index, and left ventricular ejection fraction.
Conclusions:Both clinical and genetic factors are associated with SVC arrhythmogenicity.

Full text

Circ J
doi: 10.1253/circj.CJ-17-0350
rmed as a crucial locus for the prediction of success of PV
isolation and cardioversion in people of European ances-
try, whereas it failed to show that association in those of
Asian ancestry.9–11 This study aimed to investigate the
clinical characteristics and genetic factors associated with
SVC arrhythmogenicity in consecutive AF patients under-
going catheter ablation including PV isolation.
Methods
Study Population
We evaluated 2,170 AF patients who underwent PV isola-
tion and catheter ablation for the rst time at Saitama Red
Cross Hospital (Study 1), the National Disaster Medical
Center (Study 2), and Tsuchiura Kyodo Hospital (Study 3).
All patients provided written informed consent to partici-
pate. The study protocol was approved by the ethical com-
mittees of the 3 cohorts above and of Tokyo Medical and
Dental University. The study complied with the Declaration
of Helsinki.
In Study 1, 1,534 consecutive participants who under-
went catheter ablation for AF were recruited from 2011 to
2014; among them, 1,334 participants were evaluated for
Atrial brillation (AF) can be initiated from arrhyth-
mogenic foci derived from muscular sleeves that
extend not only into the pulmonary veins (PVs) but
also into both vena cavae.1,2 Since the rst recognition that
AF triggers exist in the PVs, and subsequent trials of their
electrical isolation with catheters,1 PV isolation has become
one of the standard treatments for AF. Subsequently,
intracardiac foci in sites other than the PVs have been
found to trigger and/or drive AF,3 including the superior
vena cava (SVC).4–6 Patients with arrhythmogenic SVC
have been reported to have a smaller left atrial (LA) diam-
eter and to display coexistence of spontaneous common
atrial utter compared with AF patients with PV foci
only.6 Interestingly, patients with arrhythmogenic SVC
have long myocardial sleeves around the SVC and high
amplitude electrical potentials within them.5 These com-
mon phenotypes in arrhythmogenic SVC suggest the pos-
sible existence of genetic factors, a topic that has not been
researched.
Genome-wide association studies of AF have identied
15 associated loci in international meta-analysis studies
and 6 loci in Japanese patients to date.7,8 In particular,
chromosome 4q25 variants have been repeatedly con-
Received April 3, 2017; revised manuscript received July 6, 2017; accepted July 9, 2017; released online August 11, 2017 Time for
primary review: 31 days
Life Science and Bioethics Research Center (Y.E.), Department of Bioinformational Pharmacology (L.L., T.F.), Heart Rhythm
Center (K.H.), Department of Cardiovascular Medicine (M.I.), Tokyo Medical and Dental University, Tokyo; Cardiovascular
Division, Saitama Red Cross Hospital, Saitama (J.N., M.S.); Cardiovascular Division, National Disaster Medical Center, Tokyo
(Y.T.); Cardiovascular Division, Tsuchiura Kyodo Hospital, Ibaraki (S.M.); and Department of Nephrology, Tokyo Kyosai
Hospital, Tokyo (E.K.), Japan
Mailing address: Yusuke Ebana, MD, PhD, Life Science and Bioethics Research Center, Tokyo Medical and Dental University,
1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: ebnysk.bip@mri.tmd.ac.jp
ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp
Association of the Clinical and Genetic Factors With Superior
Vena Cava Arrhythmogenicity in Atrial Fibrillation
Yusuke Ebana, MD, PhD; Junichi Nitta, MD, PhD; Yoshihide Takahashi, MD, PhD;
Shinsuke Miyazaki, MD, PhD; Masahito Suzuki, MD; Lian Liu, MD; Kenzo Hirao, MD, PhD;
Eiichiro Kanda, MD, PhD; Mitsuaki Isobe, MD, PhD; Tetsushi Furukawa, MD, PhD
Background: Atrial fibrillation (AF) can be initiated from arrhythmogenic foci within the muscular sleeves that extend not only into
the pulmonary veins but also into both vena cavae. The superior vena cava (SVC) is a key target site for catheter ablation. Patients
with SVC-derived AF often lack the clinical risk factors of AF.
Methods and Results: We conducted a meta-analysis of the clinical and genetic factors of 2,170 AF patients with and without SVC
arrhythmogenicity. In agreement with previous reports, the left atrial diameter was smaller in AF patients with SVC arrhythmogenic-
ity. Among 6 variants identified in a previous genome-wide association study in Japanese patients, rs2634073 and rs6584555 were
associated with SVC arrhythmogenicity. This finding was confirmed in our meta-analysis using independent cohorts. We also found
that SVC arrhythmogenicity was conditionally dependent on age, body mass index, and left ventricular ejection fraction.
Conclusions: Both clinical and genetic factors are associated with SVC arrhythmogenicity.
Key Words: Atrial fibrillation; Meta-analysis; Single-nucleotide polymorphism; Superior vena cava arrhythmogenicity
ORIGINAL ARTICLE
Arrhythmia/Electrophysiology
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EBANA Y et al.
inserted through the right jugular vein for pacing and
recording; 4-electrode catheters were positioned in the
SVC, right atrium, coronary sinus (CS) and right ventricle
throughout the procedure.
Assessment of SVC Arrhythmogenicity
SVC arrhythmogenicity was conventionally dened as
ectopy in the SVC initiating AF despite repeated PV isola-
tion. In addition, SVC arrhythmogenicity was assessed with
drug challenge and pacing maneuvers. A mapping catheter
was placed in the SVC to map the circumferential SVC
region using CT or transesophageal echocardiography as
a reference (Figure 1). After PV isolation, the induction of
atrial arrhythmias was attempted by infusion of high-dose
isoproterenol (ISP), followed by atrial burst pacing from
the pacing catheter in the CS. We defined an arrhyth-
mogenic SVC as follows: (1) ectopy in the SVC initiating
AF, (2) frequent ectopy from the SVC, or (3) AF in the
SVC.5,6,12 We also dened it as (4) ectopy in the SVC initi-
ating AF after repeated PV isolation and AF ablation.
Follow-up
All patients were continuously monitored with in-hospital
ECG for several days after the procedure. Patients were
followed up at the outpatient clinic at least every 3 months
and evaluated with ECG and 24-h Holter monitoring. No
anti-arrhythmic agents were prescribed after a 3-month
blanking period. Recurrence was generally dened if AF
SVC arrhythmogenicity. No SVC arrhythmogenicity was
found in 1,028 patients (non-SVC patients), and SVC
arrhythmogenicity was found in 306 patients (SVC patients).
The numbers of patients with paroxysmal AF and persistent
AF were 919 and 353, respectively. The criteria used to
dene arrhythmogenic SVC are described later.5,6
The additional cohorts for the meta-analysis of SVC
study were Study 2 and Study 3. All of the 268 paroxysmal
AF patients who underwent PV isolation in Study 2 were
recruited from 2012 to 2014. All participants in Study 3
were recruited as previously described for another clinical
study on SVC arrhythmogenicity.6 The 568 patients gave
written informed consent for genetic testing.
Mapping and Ablation Protocol
Catheter ablation was performed in all 3 cohorts using
a common protocol.5,6,12 In brief, all anti-arrhythmic
agents were discontinued ≥5 half-lives prior to the proce-
dure. Transesophageal echocardiography was performed
to exclude atrial thrombi after at least 1 month of antico-
agulant administration. Surface electrocardiography and
bipolar intracardiac electrography were continuously mon-
itored and recordings were stored in a computer-based
recording system (Labsystem Pro, Boston Scientic Inc.,
Boston, MA, USA Study 1; and Bard Electrophysiology,
Lowell, MA, USA Studies 2 and 3). The intracardiac elec-
trograms were ltered from 30 to 500 Hz. A 7-Fr 20-pole
3-site (7-Fr 14-pole 2-site in Study 3) mapping catheter was
Figure 1. Outline of mapping proce-
dure for superior vena cava (SVC)
arrhythmogenicity. (Upper) Anterior-
posterior and left anterior oblique
views of the configuration of the multi-
electrode catheters. (Lower) Repre-
sentative case. A circular mapping
catheter was placed in the SVC. Atrial
fibrillation initiation originated from the
SVC. APC, atrial premature contrac-
tion; CS, coronary sinus; ETP, esoph-
ageal temperature probe; LPV, left
pulmonary vein; RA, right atrium; SR,
sinus rhythm; TA, tricuspid annulus.
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Two SNPs Associated With SVC Arrhythmogenicity
Table 1. Clinical Background of Study Patients With SVCA
AF without SVCA AF with SVCA P value
Study 1 n=1,028 n=306
Sex (female %) 24.4 32.8 0.003
Age (years) 61.9±13.4 60.1±15.7 0.04
Age at onset (years) 57.3±14.0 54.7±16.0 0.006
BMI (kg/m2) 24.01±3.22 23.16±3.72 0.0004
HTN (%) 51.2 43 0.007
DM (%) 11.2 7.4 NS
CHF (%) 10.4 5.5 0.008
AF (Paf/Pef/Caf) (%) 68.7/26.0/5.3 69.5/28.0/2.5 NS
Exposure duration (year) 4.38±5.01 5.03±5.57 NS
LAD (mm) 37.12±6.91 35.64±7.059 0.003
EF (%) 64.31±11.4 66.1±10.4 0.019
Recurrence (%) 10 16.5 0.002
Study 2 n=239 n=29
Sex (female %) 30.2 39.4 NS
Age (years) 64.9±10.1 64.3±12.1 NS
Age at onset (years) NA NA
BMI (kg/m2) 23.40±3.15 23.1±4.96 NS
HTN (%) NA NA
DM (%) NA NA
CHF (%) NA NA
AF (Paf/Pef) (%) 98.5/1.5 96.9/3.1 NS
Exposure duration (year) 5.02±11.28 17.42±38.66 0.086
LAD (mm) 37.40±5.72 34.45±5.53 0.005
EF (%) 65.00±8.22 67.72±6.24 NS
Recurrence (%) NA NA
Study 3 n=546 n=22
Sex (female %) 23 31.8 NS
Age (years) 62.6±9.9 60.6±9.5 NS
Age at onset (years) NA NA
BMI (kg/m2) 24.52±3.58 23.59±3.76 NS
HTN (%) 45.7 36.3 NS
DM (%) 9.5 9.1 NS
CHF (%) 8.6 9 NS
AF (Paf/Pef/longPsAF) (%) 63.4/20.8/15.8 72.7/13.6/13.6 NS
Exposure duration (year) NA NA
LAD (mm) 40.51±6.15 38.09±4.67 0.075
EF (%) 63.84±8.81 65.47±6.71 NS
Recurrence (%) NA NA
AF, atrial fibrillation; BMI, body mass index; Caf, chronic atrial fibrillation; CHF, chronic heart failure; DM, diabetes
mellitus; EF, ejection fraction; HTN, hypertension; LAD, left anterior descending; longPsAF, long standing atrial fibril-
lation; Paf, paroxysmal atrial fibrillation; Pef, persistent atrial fibrillation; SVCA, superior vena cava arrhythmogenicity.
Table 2. SNP Genotyping Study Patients With SVCA
Study 1 Study 2 Study 3
βP value βP value βP value
PRRX1 1.17 0.073
– – – –
CAV1 1.05 0.6
– – – –
CUX2 0.95 0.62
– – – –
NEURL 0.72 0.003
0.73 0.26 0.66 0.26
ZFHX3 1.11 0.25
– – – –
4q25 1.56 0.00046 1.87 0.13 1.42 0.41
GRS 9.93
1.59×10−6 10.31
0.075 1.66 0.52
SNP, single-nucleotide polymorphism; SVCA, superior vena cava arrhythmogenicity.
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EBANA Y et al.
Japanese population.7,8 We validated all genotyping results
for the 6 loci with capillary sequencing for 24 AF individuals
in this study. The result of the Invader assay coincided
completely with that of sequencing. To guarantee the quality
control for SNP genotyping, we calculated the Hardy-
Weinberg equilibrium, comparing the genotypic frequency
of the AF cases with previously published data.7,8
Statistical Analysis
The associations of SVC arrhythmogenicity with the vari-
ants were analyzed using logistic regression modeling (SPSS
version 19, Chicago, IL, USA). We assessed whether the
loci associated with SVC arrhythmogenicity in the uni-
variate logistic analysis were also signicant after adjust-
ment for each parameter such as age, sex, body mass index
(BMI), hypertension, and LA diameter. The P-value of
could be documented by ECG.
SNP Genotyping
Genomic DNA was extracted from white blood cells and
puried in accordance with the standard manufacturer’s
protocol (Wizard® SV Genomic DNA Purication System;
Promega, Madison, WI, USA). After DNA was amplied
in multiple primer sets, genotyping of single-nucleotide
polymorphisms (SNP) was performed with an Invader
assay (Third Wave Molecular Diagnostics®, Madison, WI,
USA) using an ABI7300 (Applied Biosystems, Foster City,
CA, USA) for 6 loci: at 1q24 in PRRX1 (rs593479), 4q25
near PITX2 (rs2634073), 7q31 in CAV1 (rs1177384), 10q25
in NEURL1 (rs6584555), 12q24 in CUX2 (rs649002), and
16q22 in ZFHX3 (rs12932445). All of these have been
previously demonstrated to be associated with AF in the
Figure 2. Meta-analysis of clinical factors. Forest plots of (A) sex, (B) age, (C) body mass index, (D) left ventricular ejection frac-
tion, and (E) left atrial diameter. We performed logistic regression analysis with a random effect (RE) model.
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Two SNPs Associated With SVC Arrhythmogenicity
the SNP association study for statistical signicance was
corrected with Bonferroni’s correction (corrected P-value
<0.00833). Continuous data are expressed as the mean and
standard deviation for normally distributed variables or as
the median and 25th and 75th percentiles for non-normally
distributed variables, and were compared using Student’s
t-test or Mann-Whitney U-test, respectively. Categorical
variables were analyzed using a logistic regression model.
P<0.05 was considered statically signicant.
We computed the weighted genetic risk score (GRS) for
each individual by multiplying risk allele dosages weighted
with the respective natural logarithm of the odds ratio of
SNPs. We analyzed the association study of GRS with
univariate and multivariate logistic regression models.
Meta-analysis was performed for both categorical and
continuous data using the R statistical software environ-
ment with “metafor”. To evaluate the heterogeneity of
meta-analysis, we calculated I2, and regarded I2 >25% and/
or P<0.05 as the criteria for heterogeneity.
Results
Clinical Characteristics
Of the 1,539 consecutive patients who underwent PV isola-
tion and catheter ablation for AF, 1,334 were recruited as
patients with SVC or non-SVC arrhythmogenicity after
ISP challenge (22.9% and 77.1%, respectively). The PV
isolation and catheter procedure were successfully per-
formed for all participants. SVC isolation was carried out
successfully for these patients (Figure 1).
The clinical characteristics of the 2 groups are summa-
rized in Table 1 for the 3 individual cohorts. Compared
with patients without SVC arrhythmogenicity, those with
SVC arrhythmogenicity had fewer risk factors for AF, such
as male sex, hypertension, diabetes, and congestive heart
failure. AF onset age was younger, BMI and LA diameter
were smaller, and ejection fraction (EF) was higher. Recur-
rence after catheter ablation was also observed more
frequently in AF patients with SVC arrhythmogenicity.
SNP Genotyping
Table 2 shows the genotypic frequency in Study 1of the 6
SNP loci that were signicantly associated with AF in the
Japanese population in previous reports.7,8 We obtained
the genotyping data of 1,334 patients and achieved a suc-
cessful genotyping rate of 98.7%. The genotypic frequen-
cies were similar to those previously reported.7,8 There were
2 SNPs, rs2634073 in chromosome 4q25 and rs6584555 in
NEURL1, that were signicantly associated with SVC
arrhythmogenicity (Study 1, P=0.00046 and 0.0030, respec-
Figure 3. Meta-analysis of SNP genotypes. Forest plots of
rs2634073 (A), rs6584555 (B) and genetic risk score (C). We
performed logistic regression analysis with a random effect
(RE) model. SNP, single-nucleotide polymorphism.
Table 3. Meta-Analysis of Clinical and Genetic Factors in Study Patients With SVCA
P value Estimate SE I2Test for heterogeneity
Sex 8.47×10−4 0.415 0.124 0.00 Q=0.0231, P=0.988
Age 0.0328 −1.651
0.773 0.00 Q=0.320, P=0.851
BMI 5.57×10−5 −0.805
0.2
0.00 Q=0.641, P=0.725
EF 2.12×10−3 1.918 0.624 0.00 Q=0.311, P=0.855
LA diameter 5.72×10−5 −1.897
0.471 0.16 Q=1.954, P=0.376
rs2634073 1.27×10−4 0.447 0.116 0.00 Q=0.305, P=0.858
rs6584555 5.80×10−4 −0.354
0.103 0.00 Q=0.692, P=0.707
GRS 5.20×10−7 0.0424 0.0084 0.00 Q=0.294, P=0.863
LA, left atrium. Other abbreviations as in Table 1.
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EBANA Y et al.
tract, including the LA chamber.14,15 More recent studies
have revealed that PITX2 plays a crucial role in regulating
a variety of ion channels and gap junction channels as a
transcription factor.16,17 Two atrial-specic conditional
knockout mice lines (Sox2-Cre-Pitx2 and Nppa-Cre-Pitx2)
aected their arrhythmogenicity through the calcium-
handling pathway and WNT signaling.18 By contrast, the
function of NEURL1, an ubiquitin E3 ligase in cardio-
myocytes, remains unknown. The suppression of NEURL1
expression in zebrash with morpholino leads to shortening
of the action potential (AP) duration. NEURL1 has been
suggested to regulate the metabolism of ion transporters.
The closest genes, PITX2 for rs2634073 and NEURL1 for
rs6584555, interact with each other as previously described.8
These proteins regulate the prole of ion transporters or
change AP duration. Hence, we speculate that reduced
PITX2 and NEURL1 expression in patients with genetic
risk for SVC arrhythmogenicity could cause AF suscepti-
bility by AP duration shortening and disorganized proles
of genes and proteins.
We also studied the eect of genotype on gene expres-
sion using GTEx. NEURL1 includes 10 eQTLs, 2 of which
are in linkage disequilibrium with rs6584555. On the other
hand, no eQTL of PITX2 has ever been reported. According
to published data, NEURL1 expression is decreased with
the risk allele of rs6584555.
Study Limitations
This study has 2 limitations. First, the protocols for the
assessment of SVC arrhythmogenicity were not completely
identical in the 3 cohorts. Nevertheless, we identied at
least 2 SNPs that were associated with SVC arrhythmoge-
nicity. Second, we had no data about the properties of the
SVC, such as the length of the myocardial sleeves or the
amplitude of electrical potentials. Analysis of the associa-
tion between such SVC properties and genotype variants
may provide important clues to the mechanism of AF
onset.
Conclusions
Among SNP variants identied previously in genome-wide
association studies of AF in Japan, we found rs2634073
and rs6584555 to be associated with SVC arrhythmogenic-
ity. Meta-analysis of 3 patient cohorts showed that those
with SVC arrhythmogenicity had normal LA diameter and
high frequency of risk alleles rs2634073 and rs6584555.
These variants are located in the PITX2 and NEURL1
loci. NEURL1 expression was downregulated in the left
atrial appendage according to the number of risk allele of
rs6584555 in the GTEx portal site. We speculate that AP
duration dispersion caused by the suppression of NEURL1
in SVC tissue of patients with the risk genotype could be
the cause of arrhythmogenic SVC.
Acknowledgments
We thank Koji Higuchi at Hiratsuka Kyosai Hospital and Tatsuhiko
Tsunoda at Tokyo Medical and Dental University for their advice on
SVC properties and statistical methods. We also express our gratitude
to the study participants and the doctors and research sta at the
three study sites.
Disclosure
No conicts of interest to disclose.
tively; Table 2). We also performed a subanalysis of the asso-
ciation between the 2 SNPs and SVC arrhythmogenicity in
males and females. Both SNPs were signicant in males
(rs2634073, P=0.00051, β=1.78 and rs6584555, P=0.022,
β=0.72), but neither was signicant in females (rs2634073,
P=0.089, β=1.4 and rs6584555, P=0.21, β=0.78).
To calculate GRS, we combined the data for the 2 SNP
genotypes. GRS was also signicantly associated with SVC
arrhythmogenicity (P=1.59×10−6). GRS was also associ-
ated with SVC arrhythmogenicity in the multivariate logis-
tic analysis adjusted for parameters such as age, sex, BMI,
hypertension, and LA diameter (P=0.0020, β=1.696).
Meta-Analysis of LA Diameter and Genotype Frequency
We performed a meta-analysis of all clinical (Figure 2A–E)
and genetic factors (Figure 3A–C) available in the 3 cohorts
(Table 3). LA diameter correlated negatively with SVC
arrhythmogenicity.6 This meta-analysis conrmed the
association of LA diameter with SVC arrhythmogenicity
(Figure 2E, Table 3; P=5.72×10−5, I2=15.6%). Otherwise,
we found a signicant dierence in sex, age, BMI, and EF
between the 2 groups (Figure 2A–D). As for the 2 possible
variants, although the genotypic frequency of rs2634073
varied in the 3 cohorts, the overall association was signi-
cant (Figure 3A, Table 3; P=1.27×10−4, I2=0.0%). The geno-
typic frequency of rs6584555 was consistent in the 3 cohorts
and signicantly associated with SVC arrhythmogenicity
(Figure 3B, Table 3; P=5.80×10−4, I2=0.0%). After combin-
ing the 2 variants, the calculated GRS was also signicantly
associated (Figure 3C, Table 3; P=5.2×10−7, I2=0.0%).
Effect of rs6584555 Genotype on the Expression of NEURL1
To investigate the eect of these variants on the closest
gene expression, we sorted the eQTL in the GTEx portal
site (https://www.gtexportal.org) and found 10 eQTLs that
change NEURL1 expression. Among them, rs12253987
and rs7900994 were in linkage disequilibrium with
rs6584555 (D Prime 0.889 and 1.0, respectively) in the
HapMap project and their risk allele decreased NEURL1
expression (eect size −0.35, -value 0.0000059; eect size
−0.46, -value 0.0000072; Table S1).
Discussion
Recent studies have shown that the anatomical5 and clini-
cal6 characteristics of patients with arrhythmogenic SVC
are dierent from those without arrhythmogenic SVC; the
former have a longer myocardial SVC sleeve and smaller
LA diamter. In the current study, we tested the hypothesis
that patients with arrhythmogenic SVC would also have a
genetic ngerprint dierent from the others. Therefore, we
conducted a meta-analysis of 3 cohorts to investigate the
association between SNP variants identied in genome-
wide association studies for AF and SVC arrhythmogenic-
ity. Using data from subjects who underwent catheter
ablation for AF, we found 2 SNP variants that were sig-
nicantly associated with SVC arrhythmogenicity.
The genes closest to the 2 SVC variants we found were
PITX2 in 4q25 and NEURL1 in 10q24. PITX2c was origi-
nally reported as a left-right determinant in cardiac devel-
opment.13 In animal studies, Pitx2 expression can be
observed in the heart regions arising from the secondary
heart eld. Although it is downregulated in the ventricular
chambers, high and robust expression is maintained in the
atrial chambers and in discrete components of the inow
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Two SNPs Associated With SVC Arrhythmogenicity
predict recurrence after catheter-based atrial brillation ablation.
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Montgomery J, et al. Common genetic variants and response to
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al. High atrial debrillation threshold with internal cardioversion
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Supplementary Files
Supplementary File 1
Table S1. NEURL1 eQTL in GTEx portal site
Please nd supplementary le(s);
http://dx.doi.org/10.1253/circj.CJ-17-0350
Grant Support
This work was supported by a Grant from Tailor-made Medical
Treatment Program (1K157) and a Grant-in-Aid (23790841) from
Ministry of Education, Culture, Sports, Science and Technology of
Japan.
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