Efficacy of pulmonary vein isolation by cryoballoon ablation in patients with paroxysmal atrial fibrillation.

Abstract

Radiofrequency ablation of pulmonary veins (PVs) has emerged as an effective treatment for patients with paroxysmal atrial fibrillation (AF). However, serious complications raise concern about an even wider application. In terms of safety, cryoenergy has advantages compared with radiofrequency. A new cryoenergy balloon catheter has been recently developed to make AF ablation shorter and safer.
The purpose of this study was to test the 6-month efficacy of this new device for ablation of paroxysmal AF.
Twenty-one patients with highly symptomatic paroxysmal AF, normal left atrial size, and frequent episodes of AF were included. All PVs were targeted during cryoballoon ablation. Patients received 24-hour Holter electrocardiograms (ECGs) and event recorder during follow-up after 1, 3, and 6 months.
A total of 81 (95%) of 85 PVs could be completely isolated with a single-balloon technique. Procedure time was 165 +/- 35 minutes, and fluoroscopy time was 39 +/- 9 minutes. After 6 months, 86% of the patients were free of symptomatic AF. In two of three patients with recurrence of AF, complete PV isolation has not been achieved initially. After a second procedure (1.04 procedures per patient), 90% of the patients were free of symptomatic AF. Three phrenic nerve palsies occurred during ablation of the right superior PV; two completely resolved after 6 and 9 months, and one is still persisting after 2 months.
This is the first study that reports the results of the new cryoballoon AF ablation approach showing 86% freedom from AF recurrence after 6 months. Cryoballoon PV ablation promises to be effective for patients with paroxysmal AF and normally sized left atria.

Full text

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Efficacy of pulmonary vein isolation by cryoballoon ablation in
patients with paroxysmal atrial fibrillation
Gunnar Klein, MD, Hanno Oswald, MD, Ajmal Gardiwal, MD, Ulrich Lüsebrink, MD,
Christoph Lissel, MD, Hong Yu, MD, Helmut Drexler, MD
From the Department of Cardiovascular Medicine, Hannover Medical School, Hannover, Germany.
BACKGROUND Radiofrequency ablation of pulmonary veins (PVs)
has emerged as an effective treatment for patients with paroxys-
mal atrial fibrillation (AF). However, serious complications raise
concern about an even wider application. In terms of safety,
cryoenergy has advantages compared with radiofrequency. A new
cryoenergy balloon catheter has been recently developed to make
AF ablation shorter and safer.
OBJECTIVE The purpose of this study was to test the 6-month
efficacy of this new device for ablation of paroxysmal AF.
METHODS Twenty-one patients with highly symptomatic parox-
ysmal AF, normal left atrial size, and frequent episodes of AF were
included. All PVs were targeted during cryoballoon ablation. Pa-
tients received 24-hour Holter electrocardiograms (ECGs) and
event recorder during follow-up after 1, 3, and 6 months.
RESULTS A total of 81 (95%) of 85 PVs could be completely
isolated with a single-balloon technique. Procedure time was
165 ? 35 minutes, and fluoroscopy time was 39 ? 9 minutes.
After 6 months, 86% of the patients were free of symptomatic AF.
In two of three patients with recurrence of AF, complete PV
isolation has not been achieved initially. After a second procedure
(1.04 procedures per patient), 90% of the patients were free of
symptomatic AF. Three phrenic nerve palsies occurred during ab-
lation of the right superior PV; two completely resolved after 6 and
9 months, and one is still persisting after 2 months.
CONCLUSION This is the first study that reports the results of the
new cryoballoon AF ablation approach showing 86% freedom from
AF recurrence after 6 months. Cryoballoon PV ablation promises to
be effective for patients with paroxysmal AF and normally sized
left atria.
KEYWORDS Ablation; Atrial fibrillation; Cryoablation; Cryoballoon
(Heart Rhythm 2008;5:802–806) © 2008 Heart Rhythm Society. All
rights reserved.
Introduction
Pulmonary vein (PV) isolation with radiofrequency (RF)
has been widely used for the interventional treatment of
atrial fibrillation (AF). The success rates of these procedures
vary between 65% and 85% in patients with paroxysmal AF
depending on technique used, patient selection, and experi-
ence of the center.1–3These results lead to a change in the
recent guidelines on AF, which recommend AF ablation as
a class IIa indication for patients with paroyxsmal AF with-
out structural heart disease and refractory to medical anti-
arrhythmic treatment.4However, the complication rate of
RF AF ablation is still high, and complications include PV
stenosis, thromboembolic events, pericardial effusion, left
atrial flutter, and atrioesophageal fistulae.5Cryoenergy has
potential advantages compared with RF with regard to
safety aspects. It has been shown that cryoenergy does not
lead to PV stenosis, has never been associated with atrioe-
sophageal fistula, and has a lower thrombogenicity.6–8
However, cryoablation of PVs by standard steerable cathe-
ters would be very time-consuming considering that one
single ablation point takes about 4 minutes. A new cryobal-
loon device now enables us to circumferentially isolate one
single vein, which makes cryoablation of PVs faster and
feasible. Thus, this new device raises expectations that
cryoablation of PVs might be achieved with the same speed
as with RF energy but that cryoablation is potentially asso-
ciated with a better risk profile.
The following study is the first to report the results of this
new ablation approach in patients with highly symptomatic
paroxysmal AF.
Methods
Patients with documented highly symptomatic paroxysmal
AF on two or more occasions and at least one unsuccessful
try of medical antiarrhythmic therapy were accepted (pa-
tients had symptomatic AF episodes once weekly (Table 1).
Exclusion criteria were structural heart disease or enlarged
left atria (?45 mm, parasternal long axis by echocardiog-
raphy), moderate or severe valvular heart disease, and pace-
maker implantation.
All patients received transesophageal echocardiography
at least 1 day before the procedure to exclude left atrial
thrombi. All patients were treated with a double lumen cryo-
balloon (Arctic Front; CryoCath, Montreal, Quebec, Canada),
Address reprint requests and correspondence: Priv.-Doz. Dr. Gunnar
Klein, Department of Cardiovascular Medicine, Hannover Medical School,
Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail address:
gunnarklein@yahoo.de. (Received November 24, 2007; accepted Febru-
ary 6, 2008.)
1547-5271/$ -see front matter © 2008 Heart Rhythm Society. All rights reserved.doi:10.1016/j.hrthm.2008.02.014

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either 23 mm (n ? 4) or 28 mm in size (n ? 17) as
appropriate for the size of the PVs. Both femoral veins were
used for venous access.
A single posterior transseptal approach (SR0 sheath and
BRK-1 needle, St. Jude Medical, Minnetonka, Minnesota)
was used. The SR0 sheath was removed, and the 14-Fr
FlexCath sheath was advanced over the wire into the left
atrium. Angiography of all PVs was performed via the 14-Fr
FlexCath sheath (CryoCath). Either a 23-mm or a 28-mm
cryoballoon was selected according to PV angiogram. A
decapolar mapping catheter was not used before ablation
since ablation of all veins and the associated atrial tissue
(junction) was assessed. However, after ablation, a decapo-
lar mapping catheter was used to confirm PV isolation.
Optimum position of the cryoballoon in the PV antrum was
confirmed by PV angiography and verification of vessel
occlusion (Figure 1). Cryoablation was applied for 5 min-
utes at least 2 times for each vein. When occlusion was not
as desired, the wire was changed to a different side branch
or position of balloon or the flexion of the sheath was
changed to ensure better occlusion. The ablation procedure
was always started in the left superior, then left inferior,
then right superior, and finally right inferior PV. Before
Table 1
Baseline characteristics
Patient characteristicsn
Number
Male/female
Age, years
History of AF, years
Mean interval between AF episodes, days
History of hypertension
Coronary artery disease
Number of unsuccessful antiarrhythmics
LA size, mm
CHADS2 Score
21
10/11
56 ? 6
4 ? 2
8 ? 5
14 (67)
3 (14)
2.3 ? 0.7
38 ? 3
0.6 ? 0.5
Data are mean ? standard deviation or n (%).
Figure 1
atrium and hexapolar catheter at His position. B: Intracardiac electrogram from the left superior PV (PV 1/2 to PV19/20) and the coronary sinus (CS1/2 and
CS 3/4) showing dissociated PV potentials on PV 1/2 to PV11/12. C: Conversion of AF to sinus rhythm during cyroballoon ablation in the left superior PV.
Surface ECG and intracardiac electrogram from the coronary sinus (CS 1/2, CS 3/4 and CS 5/6).
A: X-ray under angiography of the left superior PV occluded by the inflated cryoballoon (AP projection). Quadripolar catheter in the high right
803 Klein et alCryoballoon Ablation in AF

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cryoablation in the right superior vein, a quadripolar cath-
eter was placed in the superior vena cava for stimulation of
the right phrenic nerve. When loss of capture occurred,
cryoablation was immediately stopped. After all PVs were
treated with the cryoballoon, the balloon was exchanged for
the decapolar mapping catheter, and entrance block into the
veins and exit block from the veins were checked by pacing
from the decapolar mapping catheter. It was carefully
checked that the catheter was not inserted too deep into the
vein. Furthermore, exit block was also defined by the pres-
ence of slow dissociated PV rhythms (Figure 1B). Another
check-up for PV isolation was performed after waiting 30
minutes. In case of persistent conductance into PV, the
balloon was again placed in the antrum of the veins, and
contact between balloon and left atrium and vein was opti-
mized. If this did not lead to successful PV isolation, either
the smaller sized 23-mm balloon was used, which was
easier to be placed in the vein antrum, or a conventional
cryocatheter (Freezor max; CryoCath) was used to success-
fully isolate PVs.
Immediately after the procedure and the next day, pa-
tients received transthoracic echocardiography for exclusion
of pericardial effusion. During the procedure, the activated
clotting time (ACT) was kept at 350 seconds and was
checked every 30–60 minutes. After the procedure, patients
received intravenous heparin, and oral anticoagulants were
started again for at least 3 months at target international
normalized ratio (INR) 2.5. During the first 3 months, the
patients continued the antiarrhythmic medication, which has
been unsuccessful so far. Antiarrhythmic medication and
oral anticoagulation were stopped after 3 months when
patients were free of symptomatic AF episodes and Holter
electrocardiograms (ECGs) showed persistent sinus rhythm.
None of the patients received amiodarone immediately be-
fore or during follow-up. All patients received either
?-blocker or flecainide 100 mg twice daily for the first 3
months. Flecainide was used after ablation in those 11
patients who were already treated with flecainide before
ablation but without success (patients had symptomatic AF
episodes once weekly; Table 1). Three months after abla-
tion, at the latest, flecainide was stopped in all patients but
two, who had early recurrence of AF already 1 week after
the initial procedure. In all patients without recurrence of
AF, flecainide was stopped 3 months after ablation at the
latest. Beta-blocker medication was continued in five pa-
tients as part of their antihypertensive therapy or as part of
coronary artery disease (CAD) therapy. All patients re-
ceived 24-hour Holter ECGs during an outpatient follow-up
at 1, 3, and 6 months as well as an event recorder for
documentation of potential symptomatic AF episodes. Since
cryoablation has never been shown to induce PV stenosis,
transesophageal echocardiography and computed tomogra-
phy scan were only recommended if PV stenosis was sus-
pected (dyspnea at rest or exercise, cough, hemoptysis,
fever). Patients with acute phrenic nerve palsy received
chest X-ray 24 hours after the procedure, at 1-, 3-, 6-, 9-,
and 12-month intervals.
Statistics
All data are expressed as mean ? standard deviation. Com-
parisons between two groups were performed with a t-test.
For survival curve, a Kaplan-Meier analysis was performed.
Results
Baseline characteristics
Baseline characteristics are reported in Table 1. We studied
21 patients with highly symptomatic paroxysmal AF with-
out structural heart disease and normal left atrial size. Pa-
tients had a history of at least two unsuccessful class I or III
antiarrhythmics and frequent episodes of AF.
Ablation procedure
The mean duration of ablation procedure was 165 ? 35
minutes, and the fluoroscopy time was 39 ? 9 minutes.
When comparing the first six to the last six patients, fluo-
roscopy time showed a trend to decrease from 45 ? 5 to
36 ? 8 minutes (P ? .055).
We were able to isolate 81 (95%) of 85 PVs with a
single-balloon technique (17 patients with a 28-mm balloon
and four patients with a 23-mm balloon), and we had to use
a second balloon (smaller 23-mm balloon in two patients
and in one patient a conventional Freezor max 6-mm cryo-
catheter for isolation of the inferior parts of the right inferior
PV) in three cases. Nevertheless, we were not able to com-
pletely isolate the right superior PV in one patient and the
right inferior PV in another patient.
The number of cryoablations for each vein did not differ
between left and right PVs or between superior or inferior
veins (Table 2). The minimum temperature achieved by
cryoballoon ablation was not different in the superior or
inferior and right or left PVs (Table 3). However, there was
a trend for a higher minimum temperature achieved in the
right inferior PV.
Success rate
The efficacy of cryoballoon PV isolation is shown in Figure
2. During a mean follow-up of 172 ? 60 days, we had three
patients with recurrence of symptomatic AF episodes (86%
Table 2
Number of cryoballoon ablations
Vein Number ? standard deviation
Right superior PV
Left superior PV
Right inferior PV
Left inferior PV
2 ? 1
3 ? 1
2 ? 1
3 ? 1
Table 3
Minimum temperature achieved during cryoablation (°C)
VeinTemperature ? standard deviation
Right superior PV
Left superior PV
Right inferior PV
Left inferior PV
?54 ? 10
?54 ? 7
?49 ? 10
?51 ? 9
804Heart Rhythm, Vol 5, No 6, June 2008

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success rate). Most of the recurrences occurred during the
first 10 days after ablation, and two of the three patients had
incomplete PV isolation during the initial procedure despite
touch-up with a conventional cryocatheter or a 23-mm cryo-
balloon. One patient received a second cryoballoon ablation
procedure and was free of AF thereafter. Thus, after 1.04
procedures per patient, we had a 6-month success rate of 90%.
Adverse events
We did not observe any thromboembolic event. However,
we observed three phrenic nerve palsies despite pacing the
phrenic nerve during ablation of the right superior PV to
stop ablation early in case of paralysis. Two of the three
patients were asymptomatic, and two palsies completely
resolved after 6 and 9 months (Figure 3); one is still per-
sisting after 2 months. Two were observed using a 28-mm
balloon and one using a 23-mm balloon. Median time from
start of cryoablation in the right superior PV to occurrence
of phrenic nerve palsy was 93 seconds.
Discussion
Our study is the first one to report an 86% 6-month success
rate of the new cryoballoon AF ablation approach in pa-
tients with paroxysmal AF and normally sized left atria.
Although the success rate for RF AF ablation has im-
proved during the last 10 years, a variety of procedure-
related complications including thromboembolic events, PV
stenosis, left atrial flutter, and atrioesophageal fistula for-
mation still raise concern about an even wider application of
this treatment, particularly in low-volume centers.5,9–11With
respect to safety, cryoenergy has some potential advantages
comparedwithRFenergy.6,7,12First, we have recently shown
that lesions created by cryoablation are different from le-
sions created by RF energy.13Cryoablation lesions appear
sharply defined with less endothelial damage and surface
thrombosis in contrast to RF lesions, where this is a com-
mon phenomenon.7Second, when cryoablation is started,
the catheter sticks to the wall because of ice crystal forma-
tion and cannot move on the endocardial surface, ensuring
a stable catheter position. Third, delivery of RF lesion
within venous structures such as the coronary sinus or PV is
associated with a risk of venous stenosis, endoluminal
thrombosis, and perforation, possibly leading to tamponade
or damage to adjacent arterial structures. Cryothermal en-
ergy has clearly proven to be less harmful in this respect.14
However, cryoenergy applied with a conventional cryo-
catheter is time-consuming since one focal lesion takes
about 4 times longer than it takes with RF energy. The new
development of a double lumen cryoballoon enables us to
cryoablate PVs probably as fast as it takes with RF energy
but with the advantages of cryoenergy. Larger studies will
have to show if time effectiveness and safety hold true for
cryoenergy in a direct randomized comparison.
The new approach is relatively easy to perform. When
we started our study, we observed that fluoroscopy times
decreased after only five to six procedures to a mean of
?36 minutes. To select the suitable size and achieve an
optimum position of the balloon in the antrum of the
vein, we considered PV angiography to be mandatory.
The most difficult vein to isolate with the new cryobal-
loon system was the right inferior PV because of its
proximity to the transseptal sheath. However, 95% of all
veins could be isolated with a single-balloon technique,
and in only 5% we had to use a smaller balloon or a
conventional cryocatheter. In two patients, the right su-
perior and the right inferior veins in the end were not
completely isolated, and both patients showed early re-
currence of AF during the first 10 days after ablation.
Figure 2
After 6 months, 86% of the patients were free of symptomatic AF.
Survival free from symptomatic AF, Kaplan-Meier analysis.
Figure 3
resolved.
X-rays at 24 hours (A), 3 months (B), and 6 months (C) after cyroablation with right phrenic nerve palsy. After 6 months phrenic nerve palsy
805Klein et alCryoballoon Ablation in AF

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Despite the many advantages of this new approach, ad-
verse effects occurred. In three patients, right phrenic nerve
palsies occurred, which were completely asymptomatic in
two patients; one patient suffered from dyspnea. After 6 and
9 months, two palsies completely resolved; one asymptom-
atic palsy is still persisting after 2 months. Two of the
palsies occurred during the first six procedures and might
have been avoided by a more atrial position of the balloon.
In this respect, we did not observe the size of the balloon to
be relevant because one palsy occurred with a 23-mm bal-
loon and the two others occurred with a 28-mm balloon. We
consider that, independent of balloon size, a balloon posi-
tion deep in the vein should be avoided. However, by this
technique, not all palsies will be avoidable, and sometimes
complete isolation of the right superior PV might not be
achieved. Phrenic nerve palsy is not a complication unique
to cryoablation or to the cryoballoon technique, but it has
also been described by RF and ultrasound ablation.15,16
Fortunately, it has been reported that this complication is
only temporary in the majority of the cases.17We did not
observe any other complications such as symptomatic PV
stenosis, pericardial effusion, thromboembolic events, atri-
oesophageal fistula, or left atrial tachycardia.
Our study has certain limitations. First, we included a
very specific patient population without structural heart dis-
ease, with normally sized left atria, and without evidence of
moderate tricuspid or mitral regurgitation. Our data might
not reflect the situation in patients with more diseased atria
and in patients with persistent AF. However, our study
population is representative according to the American Col-
lege of Cardiology/American Heart Association guidelines
for AF ablation.4Considering more diseased and larger left
atria, it will be increasingly important to achieve substrate
modification in the periostial atrium. Since the balloon po-
sition is achieved over a wire in the distal PV, periostial
ablation with the cyroballoon can only be achieved by
changing the angulation of the sheath and retracting the
balloon to the antrum, which, however, makes a good ve-
nous occlusion angiography more difficult and sometimes
impossible. Second, during follow-up, we checked for
symptomatic AF episodes by event recorder monitoring, but
we did not check intensively for silent episodes of AF
beyond 24-hour Holter ECG. However, the main goal in
ablation of lone AF is to relieve highly symptomatic pa-
tients from symptoms of palpitations. Silent episodes of AF
would not have any further therapeutic consequence since
all of our patients, who had a mean CHADS2-score of 0.6,
did not have any indication for oral anticoagulation.4
In summary, our study shows that cryoballoon ablation
of paroxysmal AF promises to be an effective approach and
appears to have similar success rates compared with RF
ablation after 6 months. Future studies will have to show
whether this new device is also cost-effective as first-line
treatment of paroxysmal AF without any prior antiarrhyth-
mic medication and whether cryoballoon ablation is also
able to achieve a similar substrate modification compared
with RF energy in patients with persistent AF.
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