Heart and Vessels

https://doi.org/10.1007/s00380-018-1142-4

ORIGINAL ARTICLE

Additional cryoapplications at the pulmonary vein antrum

using a 28‑mm second‑generation cryoballoon: a pilot study
of extra‑pulmonary vein ablation
Shinsuke Miyazaki1,2 · Takatsugu Kajiyama2 · Tomonori Watanabe2 · Sadamitsu Ichijo2 · Yoshito Iesaka2

Received: 11 December 2017 / Accepted: 16 February 2018

© Springer Japan KK, part of Springer Nature 2018

Abstract
Isolation areas post-28-mm cryoballoon pulmonary vein isolation (CB-PVI) are smaller than post-radiofrequency PV antrum
isolation at the left superior PV (LSPV) antrum and recurrent atrial fibrillation (AF) can originate from this area. This pilot
study evaluated the impact of additional extra-PV CB applications at the LSPV antrum following conventional CB-PVI.
Eighteen paroxysmal AF patients underwent CB-PVI with single 3-min freeze techniques. Following the CB-PVI, 2-min
CB applications were added once or twice at the LSPV antrum. Before and after extra-PV ablation, left atrial (LA) 3-D
electroanatomical maps were created. Seventy-two total PVs were successfully isolated with 4.2 ± 0.4 applications/patient
with 28-mm CBs. The mean LA posterior wall (LAPW) and non-isolated LAPW areas were 14.9 ± 3.6 and 6.9 ± 2.8 cm2,
respectively. After 1.6 ± 0.5 mean extra-PV applications, the upper non-isolated LAPW area significantly decreased from
3.3 ± 1.8 to 2.5 ± 1.8 cm2 (p < 0.001). The lowest esophageal temperatures during the extra-PV ablation were 27 °C. The
total procedure and fluoroscopic times were 72.8 ± 13.1 and 15.2 ± 5.9 min, respectively. Silent gastric hypomotility was
detected in 2/9 patients 1 day later, and mild PV stenosis was observed in 4/72 PVs 3 months later, but did not progress. At
12-month after single procedures, 16 (88.9%) patients were free from recurrent AF off antiarrhythmic drugs. A median of 8.0
[6.0–10.0] months later, PV reconnections were detected in 3/12 (25.0%) PVs. The non-isolated LAPW area was significantly
larger in the chronic than acute phase (14.3 ± 5.2 cm2, p = 0.016). This pilot study suggested the potential feasibility of addi-
tional LSPV antral cryoapplications following a conventional CB-PVI. The strategy warrants further study in more patients.

Keywords Cryoballoon · Pulmonary vein isolation · Atrial fibrillation · Catheter ablation

Introduction a segmental PVI with respect to the AF freedom after the

Since the pulmonary veins (PVs) were reported as the most
important triggers of atrial fibrillation (AF) [1], electrical
pulmonary vein isolation (PVI) has become the corner-
stone strategy of AF ablation [2]. Subsequently, multiple
studies have clarified that musculature sleeves around the
PVs are also involved in the initiation and maintenance of
AF, and that a PV antrum isolation (PVAI) is superior to
* Shinsuke Miyazaki
mshinsuke@k3.dion.ne.jp
1 and antral isolation area created by the 28-mm CB, which
Department of Cardiovascular Medicine, Fukui University,
23‑3 Shimo‑aiduki, Matsuoka, Eiheiji‑cho, Yoshida‑gun,
Fukui 910‑1193, Japan
2
Cardiovascular Center, Tsuchiura Kyodo Hospital, Tsuchiura,
Ibaraki, Japan
procedure [3–5].
The cryoballoon (CB) catheter is an anatomically based
ablation device that allows for a simplified PVI with a
favorable safety profile [6]. A prospective randomized study
demonstrated significantly fewer repeat ablation procedures
and cardiovascular rehospitalizations in addition to a com-
parable efficacy and safety, as compared to RF ablation
[7]. Currently, second-generation CB ablation has become
widely accepted in the catheter ablation of paroxysmal AF
owing to the high single procedure AF freedom [8–10].
This excellent procedure outcome could be explained by
the high durability of the electrical PVI [11, 12], and wide
is evaluated in the acute phase [13, 14]. On the other hand,
the isolation area post-CB ablation during the chronic phase
is significantly smaller than that after the PVAI using RF
ablation especially at the LSPV antrum, and recurrent AF

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could originate from this LSPV antrum [15]. These study
results suggest the potential benefit of additional CB appli-
cations at the LSPV antrum following a standard CB PVI.
Therefore, we prospectively investigated the clinical impact
of additional CB applications at the LSPV antrum following
a standard CB PVI in this pilot study.
Methods
Study population
This study consisted of 18 consecutive patients with parox-
ysmal AF who underwent their first PVI using a second-gen-
eration CB in our institute. PVI was performed with a single
balloon 3-min freeze technique using exclusively a 28-mm
second-generation CB (Arctic Front Advance, Medtronic,
Minneapolis, MN, USA) [16]. Following the CB PVI, addi-
tional CB applications were applied at the LSPV antrum.
The patients with a left common PV were not included.
AF was classified according to the latest guidelines [2].
All patients gave their written informed consent. The study
protocol was approved by the hospital’s institutional review
board. The study complied with the Declaration of Helsinki.
Mapping and ablation protocol
All antiarrhythmic drugs were discontinued for at least five
half-lives prior to the procedure. Pre-procedural cardiac
enhanced computed tomography (CT) was performed to
evaluate the cardiac anatomy. The surface electrocardiogram
and bipolar intracardiac electrograms were continuously
monitored and stored on a computer-based digital recording
system (LabSystem PRO, Bard Electrophysiology, Lowell,
MA, USA). The bipolar electrograms were filtered from 30
to 500 Hz.
The procedure was performed under moderate sedation
obtained with dexmedetomidine. An esophageal tempera-
ture probe (SensiTherm, SJM, Minneapolis, MN, USA) was
inserted into the esophagus under fluoroscopic guidance,
and the position was repeatedly adjusted to match the bal-
loon position during freezing. A 100 IU/kg body weight of
heparin was administered immediately following the venous
access, and heparinized saline was additionally infused to
maintain the activated clotting time at 250–350 s. A sin-
gle transseptal puncture was performed using an RF needle
(Baylis Medical, Inc., Montreal, QC) and 8-Fr long sheath
(SL-0, SJM). The transseptal sheath was exchanged over a
guidewire for a 15-Fr steerable sheath (Flexcath Advance,
Medtronic). A 20-mm circular mapping catheter (Lasso,
Biosense Webster, Diamond Bar, CA, USA) was used for
mapping all the PVs before and after the cryoablation to
confirm the electrical isolation. A spiral mapping catheter
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Heart and Vessels
(Achieve, Medtronic) was used as a guidewire and for PV
potentials mapping. The PV ostium was occluded by a
28-mm CB with confirmation by a contrast medium injec-
tion. A 23-mm CB was not used in any cases. This was fol-
lowed by a freeze cycle of 180 s. In order to avoid bilateral
phrenic nerve injury [17], all CB applications were applied
under diaphragmatic electromyography monitoring to antici-
pate phrenic nerve injury [16].
Evaluation of the isolation area
and extra‑pulmonary vein ablation
Following the achievement of the CB PVI, using an electri-
cal impedance-based mapping system (Ensite NavX, SJM),
we created an electroanatomical bipolar voltage amplitude
map (EAM) of the LA to assess the ablation border demar-
cation. A total of 500–1000 LA mapping points per patient
were carefully obtained with a circular mapping catheter
(Lasso) [13, 14]. Low voltage areas (LVAs) were defined as
those of < 0.5 mV according to the published data [13–15].
Then, the 3D EAM was merged onto the CT rendering.
The PV ostium was defined by a steep change in the angle
between the tubular aspect of the vein and LA wall. The
posterior LA wall surface area, post-ablation non-isolated
area, and post-ablation upper non-isolated area were calcu-
lated (Fig. 1).
Based on the EAM mapping, extra-PV ablation applica-
tions were added once or twice at the LSPV antrum (Fig. 2)
[18]. First, the Achieve catheter was placed distally into the
LSPV branch as an anchor to stabilize the CB. Following
advancing the inflated balloon over the Achieve wire, the
CB was pushed towards the posterior wall or roof at the
level of the LSPV antrum (in close proximity to the LSPV
isolation area) by a clockwise rotation of the sheath. The
Flexcath sheath was deflected to push the balloon so that
good contact was made. The optimal CB position and no
LSPV occlusion were confirmed by fluoroscopy and a con-
trast injection. This was followed by a freeze cycle of 120 s.
Repeat EAM mapping was obtained to assess the ablation
border demarcation (Fig. 3).
Second procedure
During the second procedure, an electrical PVI was eval-
uated with a 20-mm circular mapping catheter (Lasso).
Then, in cases with PV reconnections, the PVI was
achieved by a minimal focal RF ablation (SmartTouch,
Biosense Webster) where the earliest PV potential was
recorded. Subsequently, mapping of the LA was per-
formed in sinus rhythm with a 20-pole steerable mapping
catheter arranged with 5 soft radiating spines covering
a diameter of 3.5 cm (Pentaray, Biosense Webster) and
Carto 3 mapping system (Fig. 4) [15]. A total of 500–1000
Heart and Vessels

LA mapping points per patient were carefully obtained.

LVAs were defined as those of < 0.5 mV according to the
published data. A pacing protocol was undertaken dur-
ing an isoproterenol infusion and an adenosine triphos-
phate injection was delivered to identify and eliminate
non-PV triggers. Cardioversion of sustained AF was also
undertaken.

Follow‑up

No antiarrhythmic drugs were prescribed after the proce-

dure. The patients underwent continuous, in-hospital ECG
monitoring for 2–3 days following the procedure. Subse-
quently, a 14-consecutive day monitoring using an external
loop recorder (Spider Flash, Sorin) was undertaken follow-
ing discharge. The first outpatient clinic visit was 3–4 weeks
after the procedure. Subsequent follow-up visits consisted
of a clinical interview, ECGs, and/or 24 h Holter monitor-
ing every 2–3 months at our cardiology clinic. Patients with
Fig. 1  Measurement of the areas in the posterior LA. The small cir- palpitations were encouraged to use a patient activated event
cles indicate the isolation line before the extra-PV CB applications. recorder for 1 month. Recurrence was defined as any atrial
The X-marks indicate the isolation line after the extra-PV CB appli-
tachyarrhythmias lasting longer than 30 s, and early recur-
cations. PW posterior wall, LSPV left superior PV, LIPV left inferior
PV, RSPV right superior PV, RIPV right inferior PV, AP antero-pos- rence of AF was defined as a recurrence within a 3-month
terior blanking period along the latest guidelines. Procedural suc-
cess was defined as freedom from any AF recurrence with-
out any antiarrhythmic drugs administered. Repeat cardiac
CT was performed > 3 months after the procedure to evalu-
ate any PV stenosis.
Fig. 2  Representative case. a
The LSPV was successfully
isolated by a single application.
The occlusion was confirmed
by a contrast injection and the
position was optimized by the
proximal seal technique. b The
first extra-PV CB application
was added at the LSPV poste-
rior antrum. Non-occlusion was
confirmed by a contrast injec-
tion. c The second extra-PV CB
application was added at the
LSPV roof-posterior antrum. d
The pre-procedural CT of this
patient revealed a normal PV
anatomy. CS coronary sinus,
Eso esophageal temperature
probe, PA postero-anterior

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 Heart and Vessels

Fig. 3  Pre- (a) and post- (b)

extra-PV ablation images
recorded with the 3D electro-
anatomic mapping system. The
scale on the 3D mapping system
was set from 0.2 to 0.5 mV. The
area surrounded by small circles
indicates the upper non-isolated
LAPW area

Fig. 4  Voltage maps post-extra-

PV ablation during the acute
phase (a), and chronic phase
(b). The area surrounded by the
small circles indicates the non-
isolated LAPW area

Statistical analysis Table 1  Characteristics of the study population

N 18
Continuous data are expressed as the mean ± stand-
ard deviation for normally distributed variables or as the Age, years 58.9 ± 11.7
median [25th, 75th percentiles] for non-normally distrib- Paroxysmal AF, n (%) 18 (100%)
uted variables, and were compared using a Student’s t test Female, n (%) 3 (16.7%)
or Mann–Whitney U test, respectively. Categorical variables Structural heart disease, n (%) 0 (0%)
were compared using the Chi square test. A probability value Hypertension, n (%) 8 (44.4%)
of p < 0.05 indicated statistical significance. Body mass index, kg/m2 24.6 ± 3.0
LA diameter, mm 37.2 ± 3.7
LV ejection fraction, % 66.5 ± 4.9
Results Pro-brain natriuretic peptide, pg/ml 161 ± 264
Estimated GFR, ml/min/1.73 m2 77.2 ± 12.5
Procedure results and complications AF atrial fibrillation, LA left atrial, LV left ventricular, GFR glomeru-
lar filtration rate
The patient characteristics are summarized in Table 1.
In 18 patients, all 4 PVs were successfully isolated with
a total of 4.2 ± 0.4 applications with a 28-mm CB. The inferior (LIPV), right superior (RSPV), and right inferior
mean number of CB applications was 1.1 ± 0.3, 1.0, PV (RIPV), respectively. PVI was achieved with a single
1.1 ± 0.3, and 1.0 ± 0.2 for the left superior (LSPV), left freeze in 16 (88.9%) LSPVs, 18 (100%) LIPVs, 16 (88.9%)

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Heart and Vessels
RSPVs, and 17 (94.4%) RIPVs. The balloon nadir tempera-
ture was − 51.9 ± 4.5, − 47.0 ± 4.8, − 58.0 ± 2.9, and
− 55.5 ± 4.9 °C in the LSPV, LIPV, RSPV, and RIPV,
respectively. Real-time PV potential monitoring was pos-
sible in 14 (77.8%), 3 (16.7%), 12 (66.7%), and 5 (27.8%)
PVs, and the time to isolation was 42.3 ± 20.9, 25.3 ± 5.9,
31.2 ± 20.5, and 30.4 ± 2.7 s in the LSPV, LIPV, RSPV, and
RIPV, respectively. The lowest luminal esophageal tempera-
ture during the conventional CB PVI was below 15, 10, 5,
and 0 °C in 6 (33.3%), 4 (22.2%), 2 (11.1%), and 1 (5.6%)
patient, respectively.
Evaluation of the isolation area and additional
antrum applications
The EAM mapping pre- and post-extra-PV ablation was
completed in 15 patients. The quality of the mapping data
was insufficient in the remaining 3 patients. The mean
LAPW surface area, non-isolated LAPW area, and upper
non-isolated LAPW area were 14.9 ± 3.6, 6.9 ± 2.8, and
3.3 ± 1.8 cm2, respectively. A mean of 1.6 ± 0.5 extra-PV
CB applications were successfully applied at the LSPV
antrum. The nadir balloon temperature was significantly
higher and the thawing phase was significantly shorter dur-
ing the LSPV antral ablation than the conventional LSPV
ablation (Table 2). The lowest esophageal temperature dur-
ing the extra-PV CB applications was 27 °C. After addi-
tional CB applications, the upper non-isolated LAPW area
significantly decreased from 3.3 ± 1.8 to 2.5 ± 1.8 cm2
(p < 0.001). The total procedure time and total fluoroscopic
time (including mapping time before and after additional
extra-PV ablation) were 72.8 ± 13.1 and 15.2 ± 5.9 min,
respectively.
Complications
No patients experienced any symptomatic complications
related to the procedure. No patients had any phrenic nerve
injury. Nine (50.0%) patients underwent non-symptom-
driven endoscopy within 2 days of the CB ablation. No
Table 2  Parameters during the LSPV ablation and extra-PV ablation
LSPV LSPV antrum p value
N 18 28
Freezing phase
Nadir CB temperature, °C − 51.8 ± 4.5 − 37.0 ± 5.3 < 0.0001
Time to − 30 °C, s 27.0 ± 3.1 45.8 ± 18.3 < 0.0001
Thawing phase
Time to 0 °C, s 11.5 ± 5.6 3.5 ± 1.3 < 0.0001
Time to 15 °C, s 47.3 ± 13.9 16.0 ± 7.1 < 0.0001
LSPV left superior pulmonary vein, CB cryoballoon
esophageal injury was identified in any of the patients,
and silent gastric hypomotility was detected in 2 (22.2%)
patients in whom the lowest esophageal temperature was
32 and 36 °C, respectively. Follow-up CT was obtained at
a median of 3.0 [3.0–5.0] months after the procedure in all
patients. Silent mild PV stenosis (25–50%) was documented
in a total of 4/72 (5.6%) PVs (2 RSPVs and 2 LIPVs) among
4 patients. All 4 patients underwent a follow-up CT at a fur-
ther median of 6 [5.3–8.3] months later, and no progression
of the stenosis was identified.
Clinical outcomes and repeat procedures
The median follow-up period was 13.5 [12.0–14.3] months,
and all 18 patients were followed for more than 12 months.
A total of 7 (38.9%) patients experienced early recurrences
of AF within 3 months after the procedure. At 12-month
after a single procedure, 16 (88.9%) patients were free from
recurrent AF off antiarrhythmic drugs. A second procedure
was performed in 3 patients (1 for AF, 1 for common atrial
flutter, and 1 for atrioventricular nodal reentrant tachycardia)
at a median of 8.0 [6.0–10.0] months after the procedure.
During the second procedure, PV reconnections were
detected in a total of 3 (25.0%) PVs (2 LSPVs and 1 LIPV)
out of 12 PVs. All conduction resumption was success-
fully eliminated by focal applications. In the patients with
recurrent AF, AF originating from a reconnected LSPV and
AF originating from the right atrium were identified and
both were successfully eliminated. All 3 patients were free
from any atrial arrhythmias after the repeat procedure. The
isolation area could be evaluated during the second proce-
dure in the 3 patients, and a non-isolated LAPW area of
14.3 ± 5.2 cm2, which was significantly larger than that dur-
ing the acute phase (p = 0.016).
Discussion
In this pilot study, we carefully investigated the clinical
impact of additional extra-PV CB applications at the LSPV
antrum following the conventional CB PVI. We found that
(1) additional extra-PV CB applications could increase the
isolation area of the LSPV antrum by 0.8 cm2 during the
acute phase, (2) the safety, efficacy, procedural time and
fluoroscopic time of this new strategy seemed to be accept-
able, and (3) the durability of the isolation area should be
evaluated in a larger study.
Limitations of the conventional CB PVI
A high single procedure AF freedom after the second-gener-
ation CB PVI [9, 10] is generally explained by the high dura-
bility of the electrical PVI [11, 12] and wide antral isolation,
13

especially at the right PVs’ antrum [13, 14]. It is well known
that a larger isolation area is associated with a significantly
lower AF recurrence rate in RF ablation [3–5]. Yet, the iso-
lation line can be designed tailor-made in a point-by-point
RF ablation, but not in CB ablation. The disadvantage of
CB ablation is that the isolation area during the chronic
phase is smaller than that after the PVAI using RF and that
recurrent AF can originate from the LSPV antrum area that
can be isolated by an RF PVAI, but not by a CB PVI [15].
Despite the smaller isolation area with the CB ablation, the
single procedure clinical outcome was comparable between
the CB and RF ablation in a prospective randomized study
[7] presumably because of the higher durability of the PVI
after the CB ablation [19–21]. This suggests the potential
benefit of additional LSPV antral CB applications following
the CB PVI. Theoretically, large areas of modification could
be achieved by a single placement of the CB. However, with
a wider lesion set, more care is necessary to avoid collateral
damage near the posterior LA. Extra-PV CB applications
at the LIPV antrum raise the concern of esophageal injury
[22] and gastric hypomotility [23]. Kuniss et al. reported
the safety of a roof line ablation with the CB following the
PVI in an observational study. However, they focused on
persistent AF patients and did not systemically explore the
potential complications or isolation area [24]. Moreover, in
paroxysmal AF, the roof line ablation lacked a theoretical
background and required 4–6 additional CB applications.
Given these data, we evaluated the impact of extra-PV CB
applications at the LSPV antrum in this pilot study. The
freeze cycle was 2 min, the same as in the previous study
[18], considering the safety concern.
Extra‑PV cryoapplications at the LSPV antrum
In the present study, the isolation area of the conventional
CB PVI during the acute phase was wide as it was in the
prior study data [13, 14]. We found several important find-
ings. First, additional LSPV antral applications could be
safely performed with acceptable procedure and fluoroscopic
times. Collateral tissue damage near the posterior LA wall
is a risk with any technology that creates wider lesions [22,
23]. However, the lowest esophageal temperature during
the extra-PV ablation was 27 °C, and no procedure-related
complications were observed. The incidence of silent gastric
hypomotility was similar to the published data during the
conventional CB PVI [23] and no PV stenosis was observed
at the LSPVs. That is why the distance between the esopha-
gus and LA is generally some distance apart at the poste-
rior-roof LSPV antrum. Second, additional LSPV antral
applications successfully increased the isolation area by
0.8 cm2 during the acute phase. Third, the single procedure
AF freedom was acceptable and relatively high as compared
to our previous data (71.6% at 12 months) [16]. Fourth,
13
Heart and Vessels
LSPV reconnections were observed in 2 out of 3 patients
who underwent a second procedure despite additional LSPV
antral applications, suggesting that non-occlusive antral CB
applications may not increase the durability of the PVI.
Different isolation area between the acute
and chronic phases
Interestingly, in the present study, the isolation area during
the chronic phase was significantly smaller than that dur-
ing the acute phase. This reversible isolation area could be
most likely explained by the tissue edema caused by the CB
ablation. Although the reported durability is high, PV recon-
nections are observed even after a CB PVI in 20–30% of PVs
during the chronic phase [12]. A histological study dem-
onstrated that cryoablation created tissue edema around a
complete tissue destruction zone in human pulmonary tissue
[25]. We cannot differentiate the durable and reversible areas
during the acute phase. Our study results suggested that
the evaluation of the isolation area during the acute phase
overestimated the true lesion size. This issue might be more
important for extra-PV CB applications. The CB was basi-
cally developed to create contiguous circular lesion around
the PV ostium and this can be achieved by a complete PV
occlusion, sufficient tissue contact, and interruption of the
PV flow [8]. In the extra-PV CB ablation, insufficient tis-
sue contact and warming by blood flow might interfere with
the durable lesion formation. Indeed, the nadir temperature
was significantly higher in the extra-PV applications than
occluded applications. Further study is necessary to evalu-
ate the durability of the extra-PV ablation lesions [26, 27].
Study limitations
The study was a small single center pilot study and no con-
trol group was included. A prospective randomized study is
necessary to evaluate the clinical implications of additional
PV antrum applications; however, a large population might
be necessary given the high single procedure AF freedom
after the conventional CB PVI. The optimal freeze dose of
extra-PV CB applications should be further discussed.
Conclusions
The present pilot study showed that extra-PV CB applica-
tions at the LSPV antrum following a conventional CB PVI
successfully increased the isolation area. The clinical out-
come, procedural time, and fluoroscopic time of this new
strategy seem to be acceptable. The strategy would warrant
further study in more patients.
Heart and Vessels

Acknowledgements We would like to thank Mr. John Martin for his 8. Coulombe N, Paulin J, Su W (2013) Improved in vivo perfor-
help in the preparation of the manuscript. mance of second-generation cryoballoon for pulmonary vein iso-
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Compliance with ethical standards JM, Daubert JC, Mabo P, Pavin D (2014) Safety and efficacy of a
second-generation cryoballoon in the ablation of paroxysmal atrial
Conflict of interest The authors declare that they have no competing fibrillation. Heart Rhythm 11:386–393
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Hoffmann E (2014) Comparison of the first and second cryobal-
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