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JACC: CLINICAL ELECTROPHYSIOLOGY
VOL. 1, NO. 3, 2015
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http://dx.doi.org/10.1016/j.jacep.2015.02.020
Adenosine-Provoked Atrial Fibrillation
Originating From Non–Pulmonary Vein Foci
The Clinical Significance and Outcome After Catheter Ablation
Akio Kuroi, MD, Shinsuke Miyazaki, MD, Eisuke Usui, MD, Noboru Ichihara, MD, Yoshihisa Kanaji, MD,
Takamitsu Takagi, MD, Jin Iwasawa, MD, Hiroaki Nakamura, MD, Hiroshi Taniguchi, MD, Hitoshi Hachiya, MD,
Yoshito Iesaka, MD
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This article has been selected as the month’s JACC: Clinical Electrophysiology
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outcome after pulmonary vein isolation for paroxysmal atrial fibrillation.
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Manuscript received January 5, 2015; revised manuscript received February 23, 2015, accepted February 26, 2015.
128
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JUNE 2015:127–35
Non-PV Foci Revealed by an ATP Test
Adenosine-Provoked Atrial Fibrillation Originating
From Non–Pulmonary Vein Foci
The Clinical Significance and Outcome After Catheter Ablation
ABSTRACT
OBJECTIVES The goal of this study was to systematically investigate the incidence and clinical significance of
non–pulmonary vein (PV) foci revealed by adenosine/adenosine triphosphate (ATP) testing during atrial fibrillation (AF)
ablation.
BACKGROUND ATP is reported to provoke AF.
METHODS A total of 464 patients with consecutive paroxysmal AF undergoing ATP testing after PV antrum isolation
were included.
RESULTS AF originating from non-PV foci was provoked in 26 (5.6%) total patients during first (n ¼ 20) or repeat
(n ¼ 8) ablation procedures. Dormant PV conduction was also revealed by ATP testing in 6 patients. Non-PV foci were
located in the superior vena cava (SVC) (i.e., the SVC group) and atria (i.e., the atria group) in 10 and 18 (9 each in the
right and left atria) patients, respectively. In the multivariable analysis, being female was the sole independent predictor
of ATP-provoked AF originating from non-PV foci (hazard ratio [HR]: 2.52 [95% confidence interval (CI): 1.069 to 5.929];
p ¼ 0.034). After additional ablation targeting non-PV foci, freedom from recurrent AF after the last procedure was
similar between the SVC group and patients without ATP-provoked AF but was significantly lower in the atria group than
in others (p ¼ 0.0008). Atria group membership (HR: 3.725 [95% CI: 1.692 to 8.199]; p ¼ 0.001) and being female
(HR: 1.538 [95% CI: 1.189 to 1.989]; p ¼ 0.001) were significant independent predictors associated with recurrence after
the last procedure in the multivariable Cox regression model.
CONCLUSIONS ATP provoked AF originating from non-PV foci under isoproterenol in 5.6% of patients undergoing
paroxysmal AF ablation. ATP testing might be useful for identifying and eliminating AF originating from the SVC.
The atria group was associated with a poor outcome after the last procedure despite efforts to eliminate non-PV foci.
(J Am Coll Cardiol EP 2015;1:127–35) © 2015 by the American College of Cardiology Foundation.
R
adiofrequency (RF) catheter ablation of atrial
METHODS
fibrillation (AF) is an established therapy for
drug-resistant paroxysmal AF (1–3). In fact,
STUDY POPULATION. The study consisted of 464
recent guidelines include catheter ablation as a first-
consecutive patients who underwent ATP testing af-
line therapy for specific groups of patients with AF
ter a PVAI during the initial ablation procedure for
(3). Pulmonary vein antrum isolation (PVAI) is the
paroxysmal AF at our hospital. AF was classified ac-
cornerstone of AF ablation procedures (3–6), and
cording to the Heart Rhythm Society/European Heart
non–pulmonary vein (PV) foci have been established
Rhythm Association/European Cardiac Arrhythmia
as important sources of AF (7). In general, identifying
Association 2012 Consensus Statement on Catheter
non-PV foci is challenging during procedures mainly
and Surgical Ablation of AF (3). All patients provided
due to the difficulty in provoking AF. The adenosine/
written informed consent.
adenosine triphosphate (ATP) test is reportedly useful
SEE PAGE 136
for identifying dormancy after PV isolation (8–10), and
it can also provoke AF (11). However, little is known
MAPPING
about the clinical impact of ATP-provoked AF origi-
rhythmic drugs were discontinued for at least 5 half-
AND
ABLATION
PROTOCOL. Antiar-
nating from non-PV foci in the context of AF ablation.
lives before the procedure. Any atrial thrombi were
The goal of the present study was to systematically
excluded by using transesophageal echocardiogra-
investigate the incidence and clinical significance of
phy. The surface electrocardiogram and bipolar in-
ATP-provoked AF originating from non-PV foci.
tracardiac electrograms were continuously monitored
Kuroi et al.
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and the data stored on a computer-based digital
activation sequence when AF occurred dur-
ABBREVIATIONS
recording system (LabSystem PRO, Bard Electro-
ing the initial ATP test; 3) a 10-pole catheter
AND ACRONYMS
physiology, Lowell, Massachusetts). The bipolar
was placed in the lateral RA; and 4) a map-
electrograms were filtered from 30 to 500 Hz. A 7-F,
ping catheter was used for ablation. Addi-
20-pole, 3-site mapping catheter (BeeAT, Japan Life-
tional
line Co., Ltd., Tokyo, Japan) was inserted through the
eliminate non-PV foci immediately after the
right jugular vein for pacing, recording, and internal
reproducibility was confirmed. If subsequent
GP = ganglionated plexus
cardioversion. The 4 proximal electrodes, 8 middle
ATP tests still induced AF, multielectrode
HR = hazard ratio
electrodes, and 8 distal electrodes were positioned in
catheters were repositioned close to the foci
LA = left atrium
the superior vena cava (SVC), high right atrium (RA),
to localize the non-PV foci, and additional RF
PV = pulmonary vein
and coronary sinus, respectively, throughout the
applications were applied. During repeat
PVAI = pulmonary vein
procedure. The procedure was performed under
procedures at the outset, the PVs were
antrum isolation
minimal sedation with pentazocine and hydroxyzine
checked with a circumferential catheter, and
RA = right atrium
pamoate.
RF
applications
were
applied
to
AF = atrial fibrillation
ATP = adenosine triphosphate
CI = confidence interval
any reconnected PVs were reisolated. ATP
RF = radiofrequency
The ablation was performed according to a strategy
tests were undertaken with the same protocol
SVC = superior vena cava
described previously (12,13). In brief, after a trans-
as during the index procedure even in cases
septal puncture, pulmonary venography during ven-
without any PV reconnections at baseline (14). When
tricular pacing and contrast esophagography were
an arrhythmogenic SVC was identified during the
performed. Heparinized saline was infused to main-
procedure (Figure 1), an electrical isolation was per-
tain the activated clotting time at 250 to 350 s. Ipsi-
formed. The ablation endpoint was elimination of all
lateral PVs were circumferentially and extensively
SVC potentials recorded on the mapping catheter (15).
ablated by using a double-Lasso technique (Lasso,
The cavotricuspid isthmus was also ablated to create
Biosense Webster, Inc., Diamond Bar, California)
bidirectional conduction block if common atrial
guided by a 3-dimensional mapping system (CARTO 3,
flutter was identified.
Biosense Webster, Inc.). The endpoint was achievement of bidirectional conduction block between the
left atrium (LA) and PVs. RF current was delivered
point-by-point with a 3.5-mm externally irrigated
tip quadripolar ablation catheter (THERMOCOOL,
FOLLOW-UP. The patients underwent continuous, in-
hospital electrocardiogram monitoring for 2 to 4 days
after the procedure. The first outpatient clinic visit
was 3 weeks’ post-procedure. Subsequent follow-up
Biosense Webster, Inc.) with a power up to 35 W
(limited to 20 W on the posterior wall close to the
esophagus), a target temperature of #38 C, and an
F I G U R E 1 Adenosine Triphosphate Provoked Atrial Fibrillation Originating From
Superior Vena Cava
irrigation rate of 30 ml/min.
After completing the PVAI, a 30-mg bolus of ATP
was injected from the right jugular vein at least twice
to identify any non-PV foci and to unmask any
dormant PV conduction with the administration of
isoproterenol (increasing the heart rate by w10 to 20
beats/min from baseline) (10). Two circular mapping
catheters were placed in the ipsilateral PVs during the
ATP test, and the left and right PV pairs were
observed individually. Any dormant conduction was
eliminated by additional RF applications. If AF was
initiated from non-PV foci by the ATP test, attempts
were made to identify the site of the origin by
observing the initial beats at the onset of the induced
AF by using multielectrode catheters (Figure 1).
Additional ATP tests were undertaken after the
mapping catheters were repositioned as follows: 1) a
Two circular mapping catheters were placed in the ipsilateral left pulmonary veins. After
20-pole mapping catheter was inserted from the
the completion of the pulmonary vein antrum isolation, an adenosine/adenosine triphos-
jugular vein to map the SVC, high RA, and coronary
sinus; 2) a circular mapping catheter was placed in the
left atrial appendage or septum close to the transseptal
hole
129
Non-PV Foci Revealed by an ATP Test
depending
on
the
coronary
sinus
phate test was performed during sequential atrial (coronary sinus [CS]) and ventricular
(right ventricular apex [RVA]) pacing. Atrial fibrillation was initiated from the superior vena
cava (SVC) (red arrow) after atrioventricular block. LIPV ¼ left inferior pulmonary vein;
LSPV ¼ left superior pulmonary vein.
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Non-PV Foci Revealed by an ATP Test
visits consisted of clinical interviews, electrocardio-
patients, and dormant PV conduction was revealed by
grams, and 24-h Holter monitoring every 3 months at
ATP testing in 164 (35.3%) during the initial proce-
our cardiology clinic. No antiarrhythmic drugs were
dure. Among the 464 first and 115 second ablation
prescribed after the procedure. Patients with palpita-
procedures, AF originating from non-PV foci was
tions were encouraged to use patient-activated event
provoked repeatedly by ATP injections in 20 (4.3 %)
recorders for 30 consecutive days. For the detection of
and 8 (6.9 %) patients, respectively. AF was provoked
any asymptomatic events, an external loop recorder
during both the first and second procedures in
was used (SpiderFlash, Sorin Group, Clamart, France),
2 patients. Therefore, in total, ATP-provoked AF
which enabled the automatic detection of any atrial
originating from non-PV foci was observed in 26
tachyarrhythmia for 14 consecutive days (16). Recur-
(5.6%) patients. AF was initiated from non-PV foci
rence was defined according to the patient’s symp-
spontaneously, during an isoproterenol infusion, and
toms and/or if an arrhythmia lasting >30 s was
after electrical cardioversion in 7, 3, and 2 other
documented.
patients, respectively. The clinical characteristics of
STATISTICAL
ANALYSIS. Continuous
data
are
expressed as the mean SD for normally distributed
variables or as the median (25th to 75th percentiles) for
nonnormally distributed variables, and they were
compared by using a Student t test or Mann-Whitney U
test,
respectively.
Categorical
variables
were
compared by using the chi-square test. All parameters
with a significance of <0.2 in the univariable analysis
were entered into a multiple logistic regression analysis. The multivariable Cox method was used
to determine the predictors of recurrent arrhythmias. Variables whose univariable analyses had
p values <0.05 were included in the multivariable Cox
regression model. A Kaplan-Meier analysis was used to
determine the percentage of patients free from recurrence. The difference in the arrhythmia-free survival
was evaluated by using the log-rank test. The proportional hazards assumption was investigated graphically, with a test based on Schoenfeld residuals.
The following variables were evaluated in association with being arrhythmia-free after the procedure:
age, sex, body mass index, presence of structural
heart disease, hypertension, left atrial diameter, left
ventricular ejection fraction, CHADS 2 score (congestive heart failure, hypertension, age $75 years, diabetes mellitus [1 point for presence of each], and
stroke/transient ischemic attack [2 points]), CHA 2DS2VASc (congestive heart failure, hypertension, age $75
years, diabetes mellitus, stroke/transient ischemic
attack, vascular disease, age 65 to 74 years, sex
category score), pro–B-type natriuretic peptide level,
high-sensitivity C-reactive protein level, estimated
glomerular filtration rate, and ATP-provoked AF. A
probability value of p < 0.05 indicated statistical
significance.
the patients with and without ATP-provoked AF are
shown in Table 1.
In the univariable analysis, a younger age, female
sex, and higher glomerular filtration rate showed a
trend toward being associated with ATP-provoked AF
originating from non-PV foci. In the multivariable
analysis, female sex (hazard ratio [HR]: 2.52 [95%
confidence interval (CI): 1.069 to 5.929]; p ¼ 0.034)
was the sole independent pre-procedural predictor of
ATP-provoked AF originating from non-PV foci.
RESPONSE TO THE ATP INJECTION DURING THE
INITIAL PROCEDURE. Among the 20 patients in
whom AF originating from non-PV foci was provoked
by ATP injections during the initial procedure, AF
terminated spontaneously at a median of 180 s (40 to
595 s) after initiation in 9 (45.0%) patients; it persisted
and
required
electrical
cardioversion
to
be terminated in the remaining 11 (55.0%) patients.
Immediate recurrent AF after cardioversion was
observed in 4 (20.0%) patients and was initiated from
the SVC in all patients. AF was provoked before,
during, and following the occurrence of AV block
after ATP injections in 3 (15.0%), 16 (80.0%), and 1
(5.0%) patients, respectively. An AF trigger was
identified in the SVC, RA, and LA in 9 (45.0%),
5 (25.0%), and 6 (30.0%) patients, respectively
(Figure 2). In patients with AF originating from the
SVC, an electrical SVC isolation was successfully
achieved in all patients. In 11 (55.0%) patients with AF
originating from the atria, focal ablation targeting the
non-PV foci was added, and a subsequent repeat ATP
test did not provoke any AF except in 1 patient. A
transient PV reconnection was observed according to
an ATP test in 6 (30.0%) patients at the right-sided,
left-sided, and bilateral ipsilateral PVs in 1, 3, and 2
patients, respectively. These transient PV reconnec-
RESULTS
tions did not lead to the initiation of AF.
PREVALENCE AND CLINICAL CHARACTERISTICS. A
patients were free from any recurrent arrhythmias
successful PVAI was achieved in all 464 study
without any antiarrhythmic drugs at 1 year. There was
After the initial ablation procedure, 55.3% of the
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Non-PV Foci Revealed by an ATP Test
T A B L E 1 Clinical Characteristics of Patients With and Without ATP-Provoked AF
ATP-AF (þ)
(n ¼ 26 [5.6%)]
ATP-AF (–)
(n ¼ 438 [94.4%])
Univariable
p Value
Multivariable
p Value
Age, yrs
58.7 12.8
62.6 10.8
0.083
0.136
Female
11 (42.3)
121 (27.6)
0.107
0.034
1 (3.9)
50 (11.4)
0.231
SHD
Hypertension
15 (57.7)
251 (57.3)
HR
95% CI
2.52
1.069–5.929
0.969
Body mass index, kg/m2
24.0 3.8
24.3 3.7
CHADS2 score
0.73 0.96
0.79 0.93
0.745
CHA2DS2-VASc score
1.54 1.58
1.58 1.38
0.889
LA diameter, mm
39.9 5.5
40.3 5.8
0.724
LV ejection fraction, %
65.5 9.0
66.5 7.0
0.476
proBNP, pg/ml
270 356
hs-CRP, mg/dl
0.17 0.28
0.24 0.81
0.662
Estimated GFR, ml/min
77.3 17.8
71.1 19.4
0.114
0.692
332 1,033
0.801
0.393
Values are mean SD or n (%).
AF ¼ atrial fibrillation; ATP ¼ adenosine triphosphate; CHADS2 score ¼ congestive heart failure, hypertension, age $75 years, diabetes mellitus (1 point for presence of each),
and stroke/transient ischemic attack (2 points); CHA2DS2-VASc score ¼ congestive heart failure, hypertension, age $75 years, diabetes mellitus, stroke/transient ischemic
attack, vascular disease, age 65 to 74 years, sex category; CI ¼ confidence interval; GFR ¼ glomerular filtration rate; HR ¼ hazard ratio; hs-CRP ¼ high-sensitivity C-reactive
protein; LA ¼ left atrium; LV ¼ left ventricular; proBNP ¼ pro–B-type natriuretic peptide; SHD ¼ structural heart disease.
no significant difference in the freedom from recur-
whom AF was provoked by an ATP injection during
rent arrhythmias after the initial procedure between
the second procedure, AF terminated spontaneously
the patients with and without ATP-provoked AF
at a median of 75 s (30 to 300 s) after the initiation in 4
(p ¼ 0.61) (Figure 3).
(50.0%) patients; it persisted and required electrical
RESPONSE TO THE ATP INJECTION DURING THE
REPEAT PROCEDURE. Among 115 patients undergo-
ing a second procedure, PV reconnections were
observed in 98 (85.2%) patients. Among 8 patients in
cardioversion to terminate it in the remaining 4
(50.0%) patients. Immediate recurrent AF after cardioversion was observed in 3 (37.5%) patients, and AF
initiated from the SVC, RA, and LA in 1 each. AF was
provoked during AV block after an ATP injection in all
patients. An AF trigger was identified in the SVC, RA,
and LA in 1 (12.5%), 4 (50.0%), and 3 (37.5%) patients,
F I G U R E 2 Distribution of the Origins of ATP-Provoked AF
respectively (Figure 2). In the patient with AF originating from the SVC, an electrical SVC isolation was
successfully achieved. In 7 patients with AF originating from the atria, focal ablation targeting the
non-PV foci eliminated the ATP-provoked AF in 5
(62.5%) but not in 3 (37.5%) patients. No PV reconnections were provoked in any of the patients with
the ATP test.
After the second procedure, 50% of the patients
were free from recurrent arrhythmias without any
antiarrhythmic drugs at 1 year. Among the 4 patients
with
recurrent
arrhythmias,
the
ATP-provoked
AF was eliminated in 2 but not in the remaining
2 patients.
CLINICAL OUTCOME IN PATIENTS WITH ATP-PROVOKED
AF ORIGINATING FROM NON-PV FOCI. In all 26 paNon–pulmonary vein foci were identified along the crista terminalis (CT), septum, and close to the distal CS. AF ¼ atrial fibrillation; ATP ¼ adenosine triphosphate test; IVC ¼ inferior vena
cava; PW ¼ posterior wall; RIPV ¼ right inferior pulmonary vein;
RSPV ¼ right superior pulmonary vein; other abbreviations as in
Figure 1.
tients, the reproducibility of ATP-provoked AF was
confirmed, and a mean of 4.0 3.2 APT tests per
procedure were performed. No multiple non-PV foci
were observed in any patients. Freedom from recurrent AF after the last procedure was significantly
lower in the 26 patients with ATP-provoked AF
131
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Non-PV Foci Revealed by an ATP Test
F I G U R E 3 Freedom From Recurrent AF After a Single Procedure
Freedom from recurrent arrhythmias after a single ablation procedure in patients with and without ATP-provoked AF originating from
non–pulmonary vein foci during the initial procedure. Abbreviations as in Figure 2.
originating from non-PV foci during either the initial
after the last procedure in the multivariable Cox
or second procedure compared with those without
regression model.
(p ¼ 0.002) (Figure 4A). However, when the patients
with ATP-provoked AF were divided into 2 groups,
including patients with AF originating from the SVC
(i.e., the SVC group) and those with AF originating
from the atria (i.e., the atria group), the freedom from
recurrent AF after the last procedure was significantly
lower in the atria group but similar in the SVC group
compared with patients without ATP-provoked AF
(p ¼ 0.0008) (Figure 4B).
An increased age, higher CHA2DS2 -VASc score,
being female, and ATP-provoked AF originating
from non-PV foci were correlated with a recurrence
after the last procedure as identified by the univariable analysis, and being female (HR: 1.538 [95%
CI: 1.189 to 1.989]; p ¼ 0.001) and ATP-provoked AF
originating from non-PV foci (HR: 3.328 [95% CI:
1.632 to 6.783]; p ¼ 0.001) were the significant factors in the multivariable Cox regression model
DISCUSSION
MAJOR FINDINGS. First, the ATP test under an
isoproterenol infusion provoked AF originating from
non-PV foci in 5.6% of patients undergoing paroxysmal AF ablation. Second, being female was the sole
independent predictor of ATP-provoked AF originating from non-PV foci. Third, the SVC was the
important source (38.2%) of non-PV foci, revealed
by results of the ATP test, which can aid in the
identification of an arrhythmogenic SVC during the
procedure. Fourth, ATP-provoked AF originating
from the atria was the independent predictor associated with a recurrence of arrhythmia after the last
procedure.
ADENOSINE/ATP TEST IN THE CONTEXT OF AF
(Table 2). Further analysis revealed that the atria
ABLATION. The adenosine/ATP test has been used
group was significantly associated with a recurrence
for the identification of the dormancy during the
after the last procedure (HR: 3.725 [95% CI: 1.692 to
initial procedure after electrical isolation (8–10). A
8.199]; p ¼ 0.001), but the SVC group was not
prospective study is ongoing to investigate the clin-
(p ¼ 0.247). Similarly, when analyzing the 115 pa-
ical implications of targeting dormant PVs by addi-
tients undergoing repeat procedures, being female
tional ablation (17). Datino et al. (18) showed that
(HR: 2.595 [95% CI: 1.095 to 6.147]; p ¼ 0.030) and
adenosine acutely restores the PV–LA conduction by
ATP-provoked AF originating from non-PV foci
hyperpolarizing the PV cells and thereby enhancing
(HR: 3.324 [95% CI: 1.284 to 8.603]; p ¼ 0.013) were
the Naþ current availability. A similar dormancy was
the significant factors associated with recurrence
also reported in PVs during the chronic phase after
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Non-PV Foci Revealed by an ATP Test
F I G U R E 4 Freedom From Recurrent AF After the Last Procedure
(A) Freedom from recurrent arrhythmias after the last ablation procedure in patients with and without ATP-provoked AF originating from non–
pulmonary vein foci. (B) Freedom from recurrent arrhythmias after the last ablation procedure in patients with ATP-provoked AF originating
from the SVC, those with ATP-provoked AF originating from the atria, and those without ATP-provoked AF. Abbreviations as in Figures 1 and 2.
the isolation (14), at the cavotricuspid isthmus, after
This finding might be explained by the difficulty in
achievement of linear conduction block (19), and in
identifying the precise foci from a single earliest beat
the SVC after isolation (20), presumably with a similar
by using conventional mapping techniques and the
mechanism.
low reproducibility of AF induction by the ATP test.
The ATP test is also useful for provoking AF
Among the 8 patients in whom AF was provoked by
during the procedure. Isoproterenol is widely used
the ATP test during the second procedure, 6 patients
to identify AF triggers, and it usually provokes
did not have any ATP-provoked AF during the initial
catecholamine-dependent arrhythmias. In the pre-
procedure, presumably due to the variable autonomic
sent study, additional ATP injections were used to
tone during the time course and the impact of the
identify non-PV foci. Recently, Tao et al. (21) reported
PVAI on the autonomic tone. Recently, Zhang et al.
that the ATP test facilitated the identification of
arrhythmogenic PVs in patients with paroxysmal AF
undergoing ablation. They showed that the majority
T A B L E 2 Factors Associated With Recurrent Arrhythmias After the Last Procedure
of ATP-induced AF originated from the PVs. In
Univariable
p Value
contrast, ATP tests were undertaken after the PVAI in
our large consecutive series, and the prevalence of
Age, yrs
ATP-provoked AF originating from non-PV foci was
Female
5.6% with isoproterenol infusions.
SHD
The identification of an arrhythmogenic SVC is
0.001
<0.001
Hypertension
0.513
Body mass index, kg/m2
0.200
ing an established effective therapy (22). In our se-
CHADS2 score
ries, the SVC was the important source of non-PV foci
revealed by ATP, and the ATP test aided in the
95% CI
Multivariable
p Value
1.043
1.017–1.070
0.124
3.039 1.906–4.843
0.001
1.348
1.162–1.564
0.417
2.802
1.392–5.643
0.001
LA diameter, mm
0.154
LV ejection fraction, %
0.840
proBNP, pg/ml
0.323
clinical outcome can be expected in cases with an
hs-CRP, mg/dl
0.065
arrhythmogenic SVC because the complete elimina-
Estimated GFR, ml/min
0.581
tion of the trigger is relatively easy by electrical
ATP-AF
0.004
isolation. In fact, the clinical outcome after the last
ATP-AF from SVC
0.247
procedure was similar in the SVC group and in those
ATP-AF from atrium
0.001
outcome was significantly poorer in the atria group.
95% CI
1.538 1.189–1.989
0.057
<0.001
identification of the arrhythmogenicity. A better
without ATP-provoked AF. Conversely, the clinical
HR
0.645
generally challenging despite electrical isolation be-
CHA2DS2-VASc score
HR
SVC ¼ superior vena cava; other abbreviations as in Table 1.
3.328 1.632–6.783
3.725 1.692–8.199
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Non-PV Foci Revealed by an ATP Test
(23) reported that 13% of ATP-induced non-PV foci
STUDY LIMITATIONS. First, the study used a ret-
were observed after PVAI. Their reported prevalence
rospective
of ATP-provoked non-PV foci was considerably
although non-PV foci were localized by using a
higher than in the present study, presumably due to
number of multielectrode catheters, identification of
the different study population. The majority of their
precise non-PV foci is challenging because of the lack
study population were women (52% female) and
of a single-beat mapping system. Third, the pure
the age was younger (mean 57.4 years) than in
impact of an ATP injection on non-PV foci could not
our study. Our study has shown that being female
be evaluated because the ATP test was undertaken
was an independent predictor of ATP-induced non-
under an isoproterenol infusion. The utility of the
PV foci and that the location of the non-PV foci was
ATP test should be evaluated and compared with
strongly associated with the clinical outcome after
other approaches for identifying non-PV foci, such as
the last procedure, which seems to be clinically
isoproterenol infusions, in a prospective clinical trial.
significant.
Fourth, the ATP test was not undertaken before the
and
nonrandomized
design.
Second,
PVAI, and thus the impact on the PVs was not
MECHANISMS OF ATP-PROVOKED AF. Adenosine is
evaluated.
a purine nucleoside closely related to adenosine5 0 -triphosphate, which is important in multiple
CONCLUSIONS
biochemical processes (24). Both exert transient
negative chronotropic and dromotropic responses on
An ATP injection under an isoproterenol infusion
the sinoatrial and atrioventricular nodes. It is well
provoked AF originating from non-PV foci in 5.6% of
known that adenosine can induce AF in clinical
patients undergoing paroxysmal AF ablation. The SVC
practice (11), and previous studies have postulated
was the origin of 38.5% of the non-PV foci revealed by
that shortening of atrial action potential duration is
ATP, which aides in identifying an arrhythmogenic
the principal mechanism of adenosine-induced AF
SVC. ATP-provoked AF originating from the atria is a
(25). In addition, adenosine has sympathoexcitatory
significant independent predictor associated with
effects mediated through a baroreflex activation and
recurrent arrhythmias after the last procedure.
chemoreceptor stimulation (26).
ACKNOWLEDGMENT The authors thank Mr. John
Another
hypothesis is
the
activation
of
the
Martin for the preparation of the manuscript.
autonomic nervous system via the ganglionated
plexus (GP). An injection of acetylcholine into the
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
GP at the PV–LA junction has been shown to acutely
Shinsuke Miyazaki, Cardiology Division, Cardio-
result in the induction of spontaneous PV ectopy
vascular Center, Tsuchiura Kyodo Hospital, 11-7
(27). The preferential role of the SVC–aorta GP in
Manabeshin-machi,
modulating the electrophysiological function of the
Japan. E-mail: [email protected].
Tsuchiura,
Ibaraki
300-0053,
SVC sleeves in canines has also been shown (28).
Adenosine and acetylcholine act on identical receptor pathways to induce antiadrenergic effects,
and hyperactivity of the SVC–aorta GP induced by
direct injection of acetylcholine can lead to rapid
firing from the SVC. Thus, adenosine can trigger
vagally mediated AF.
The reason why ATP-provoked AF was identified
more frequently in female patients is unclear from
the present data. Previous large studies showed that
the outcome after AF ablation was worse for female
patients and speculated that non-PV foci were one of
the causes of a higher recurrence rate (29,30). Differences in sex in cardiac autonomic regulation are
well known (31). Given that an ATP injection has a
strong influence on autonomic tone, it is possible
that the impact of ATP on the arrhythmia inducibility has sex differences and that residual non-PV
foci after PVAI are revealed more frequently in female patients.
PERSPECTIVES
COMPENTENCY IN MEDICAL KNOWLEGDE:
Adenosine injection provoked AF originating from
non-PV foci in 5.6% of patients undergoing paroxysmal AF ablation. The SVC was the origin of 38.5% of
the non-PV foci revealed by adenosine, which aids in
identifying an arrhythmogenic SVC. Moreover,
adenosine-provoked AF originating from the atria was
a significant independent predictor associated with
recurrent arrhythmias after the last procedure.
TRANSLATIONAL OUTLOOK: The utility of the
adenosine test should be evaluated and compared
with other approaches for identifying non-PV foci,
such as isoproterenol infusions, in a prospective
clinical trial.
Kuroi et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 3, 2015
JUNE 2015:127–35
Non-PV Foci Revealed by an ATP Test
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KEY WORDS adenosine, adenosine
triphosphate, atrial fibrillation, catheter
ablation, non–pulmonary vein foci
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