REVIEW

The Biophysics and Biomechanics of Cryoballoon

Ablation
JASON G. ANDRADE, M.D., MARC DUBUC, M.D., PETER G. GUERRA, M.D., LAURENT
MACLE, M.D., BLANDINE MONDÉSERT, M.D., LÉNA RIVARD, M.D., DENIS ROY, M.D.,
MARIO TALAJIC, M.D., BERNARD THIBAULT, M.D., and PAUL KHAIRY, M.D., PH.D.
From the Electrophysiology Service, Department of Cardiology, Montreal Heart Institute, Université de Montréal,
Montreal, Canada

Recent clinical and preclinical studies have demonstrated that cryothermal ablation using a balloon
catheter (Artic FrontR
, Medtronic CryoCath LP, Pointe-Claire, Canada) provides an effective means of
achieving pulmonary vein isolation. This review explores the biophysics and biomechanics of cryoballoon
ablation. Components of the cryoballoon catheter system are examined, mechanisms of cryothermal
injury are summarized, and potential advantages of cryoballoon technology over standard radiofrequency
ablation in isolating pulmonary veins are discussed. Practical aspects of biophysics and biomechanics
relevant to the clinical electrophysiologist are emphasized, particularly with regards to the selection
of the most appropriate cryoballoon catheter and minimizing peri-procedural complications. (PACE
2012;XX:1–7)
atrial fibrillation, catheter ablation, cryoablation, cryoballoon

Introduction coagulation and tissue necrosis, the objective

Atrial fibrillation (AF) is the most common
sustained cardiac arrhythmia and is associated
with reductions in quality of life, functional
status, cardiac performance, and overall sur-
vival.1 Catheter ablation, which is centered on
electrical isolation of triggering foci within the
pulmonary veins (PVs) through circumferential
lesions around PV ostia, has been shown to
result in sustained improvements in quality of
life, decreased hospitalizations, and, potentially,
improved survival.2–4 Recent clinical and preclin-
ical studies have demonstrated that cryothermal
ablation using a balloon catheter (Arctic Front R
, the selection of the most appropriate cryoballoon
Medtronic CryoCath LP, Pointe-Claire, Canada)
provides an effective means of achieving PV
isolation.5 Cryothermy as an ablation energy
source offers several distinct advantages when
compared to the current standard of care. While
radiofrequency (RF) energy results in hyperther-
mic cellular injury through a combination of
Financial Support: Dr. Khairy is supported by a Canada
Research Chair in Electrophysiology and Adult Congenital
Heart Disease.
Conflict of Interest Disclosure: Dr. Dubuc is a consultant for
Medtronic.
Address for reprints: Paul Khairy, M.D., Ph.D., Electrophysi-
ology Service, Montreal Heart Institute, 5000 Belanger St. E,
Montreal, QC, Canada, H1T 1C8. Fax: 514-593-2551; e-mail:
paul.khairy@umontreal.ca
Received March 28, 2012; accepted April 2, 2012.
doi: 10.1111/j.1540-8159.2012.03436.x
of cryothermal ablation is to freeze tissue in a
discrete and focused fashion in order to destroy
cells in a precisely targeted area.6
This review explores the biophysics and
biomechanics of cryoballoon ablation (CBA).
Components of the cryoballoon catheter system
are examined, mechanisms of cryothermal injury
are summarized, and potential advantages of CBA
over standard RF ablation in isolating PVs are
discussed. Practical aspects of biophysics and
biomechanics relevant to clinical electrophysiolo-
gists are emphasized, particularly with regards to
catheter.7,8
The Anatomy and Physiology of a Cryoballoon
The Arctic Front R
CBA system (Medtronic
CryoCath LP) consists of a steerable 10.5-Fr
catheter with distally mounted polyurethane
and polyester balloons. It is introduced to the
left atrium via a 15-Fr deflectable delivery
sheath (FlexCath R
; Medtronic CryoCath LP; 12-
Fr inner diameter) and connected to an external
CryoConsole R
(Medtronic CryoCath LP), which
houses the coolant.
The cryoballoon catheter (Fig. 1) contains: (1)
An intake lumen (injection tube) that permits the
injection of cryorefrigerant to the inner balloon;
(2) An exhaust lumen to facilitate its removal;
(3) A central lumen that permits a guide-wire
for positioning/support, a small-diameter circular
diagnostic catheter for monitoring of pulmonary
venous potentials, the injection of contrast to

C 2012, The Authors. Journal compilation 

 C 2012 Wiley Periodicals, Inc.

PACE, Vol. 00 2012 1

 ANDRADE, ET AL.
Figure 1. Anatomy of a Cryoballoon catheter (Courtesy:
Medtronic).
ensure adequate positioning/PV occlusion, and
PV pressure monitoring; (4) A thermocouple on
the central shaft near the proximal end of the
balloon to facilitate inner balloon temperature
monitoring; and (5) A dual pull-wire mechanism
integrated into the handle of the catheter that
facilitates catheter deflection. In addition, the
catheter contains several redundant safety sys-
tems. For example, a constant vacuum is applied
between the inner and outer balloon to ensure
the absence of cryorefrigerant leakage into the
systemic circulation in the event of a breach in
the integrity of the inner balloon.
Ablation is realized through the delivery of
pressurized cryorefrigerant (nitrous oxide; N2 O)
to the distal aspect of the inner balloon via an
ultrafine injection tube. As the refrigerant enters
the distal inner balloon it undergoes a liquid-to-gas
phase change. Just prior to release into the inner
balloon, the cryorefrigerant is further pressurized
through a restriction tube that is designed to
maximize the temperature drop (to –80◦ C) via
the Joule-Thompson effect (i.e. further cooling
that arises when a highly compressed nonideal
gas expands into a region of low pressure).
The cryorefrigerant then absorbs heat from the
surrounding tissue before returning to the console
through a lumen maintained under vacuum.
Lesion Formation with Cryoablation
Lesion formation with cryothermy is based
around the generation of hypothermia at the
catheter-tissue interface and can be divided in
three sequential stages: the freeze/thaw phase, the
hemorrhagic-inflammatory phase, and the replace-
ment fibrosis phase.6 During the first phase, pro-
gressive hypothermia results in cardiomyocytes
becoming less fluid as their metabolism slows,
2 2012
ion pumps lose transport capabilities, and the
intracellular pH becomes more acidic. In general,
the early effects are transient provided that the
duration of nonfreezing cooling temperatures does
not exceed a few minutes. Thereafter, progressive
cooling is associated with the formation of
ice crystals. Initially, as freezing temperatures
drop below –15◦ C, there is ice crystal formation
exclusively in the extracellular space. Progressive
cooling to below –40◦ C results in the formation
of intracellular ice crystals. Although these ice
crystals are associated with a degree of mechanical
cellular disruption, the predominant mechanism
of cellular injury is biochemical. Triggered by the
formation of ice crystals, the extracellular space
becomes hypertonic relative to the intracellular
space. In an attempt to reestablish osmotic equilib-
rium, there is a compensatory egress of water from
the intracellular to the extracellular space, with
subsequent cellular shrinkage. Furthermore, the
newly established osmotic gradient precipitates a
diffusion gradient between the extracellular and
intracellular spaces, resulting in the net movement
of H+ ions out of the cell, and the migration of
solute ions into the cell. Concomitant increase
in the intracellular saline concentration with a
reduction in intracellular pH results in cellular
protein damage, enzyme system impairment, and
adverse effects on the lipoprotein components of
the plasma membrane containing the cell and its
organelles. Of all the cytoplasmic components,
the mitochondria are particularly sensitive and
are the first structures to suffer irreversible
damage.
Moreover, concurrent to the intra- and extra-
cellular ice formation is a microvascular injury
effect.6 This progressive microcirculatory failure
occurs due to a cascade of events (endothelial
layer destruction causing vessel walls to become
porous, interstitial edema, platelet aggregation,
microthrombi, and ultimately vascular congestion
and obliteration) resulting in cessation of blood
flow, and subsequent ischemia. Upon completion
of the freezing phase, the tissue passively returns
to body temperature resulting in a “thawing
effect.” This is an important component of
cryoablation, as rewarming results in a hyperemic
vascular response as well as causing the intra-
and extracellular ice crystals to enlarge and
fuse into larger masses, thus extending cellular
destruction. The thawing phase is followed by a
period of hemorrhage and inflammation. As the
microcirculation is restored to previously frozen
tissue, edema ensues. The fluid traverses dam-
aged microvascular endothelial cells, resulting
in ischemic necrosis. Lastly, in the final phase
of cryoinjury, there is replacement fibrosis and
apoptosis of cells near the periphery of the frozen
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 BIOPHYSICS AND BIOMECHANICS OF CRYOBALLOON ABLATION
tissue, which gives rise to a mature lesion within
weeks.6
Advantages of Cryoablation in AF
Given these mechanistic differences, the use
of cryothermal energy for PV isolation has several
potential advantages over RF energy: (1) Freeze-
mediated catheter adhesion results in increased
catheter stability, which is particularly advan-
tageous when ablating technically challenging
regions such as the ridge between left-sided
PVs and the appendage. Moreover, the increased
stability could be expected to result in less
collateral damage to nearby structures, such as the
PVs or esophagus.6 (2) Cryoablation results in the
creation of well-demarcated homogeneous lesions
that are less arrhythmogenic than the ragged
indistinct lesions associated with RF ablation.6,9
(3) Mature lesions resulting from cryoablation
demonstrate preservation of tissue ultrastructural
integrity. In the immediate term, preservation
of the connective tissue matrix should result
in a lower risk of myocardial perforation and
esophageal injury during ablation.6,10 In the
longer term, given the minimal tissue contraction
observed with lesion healing, it can be expected
that lesions produced with cryoablation should
result in a lower incidence of PV stenosis.11,12
(4) Lesions produced with the application of
cryoenergy results in minimal endocardial surface
disruption and are thus less thrombogenic than
those produced with RF energy.9,13 Moreover,
cryoablation appears to activate platelets and the
coagulation cascade to a lesser degree than RF
ablation.14 As such, cryoablation is associated
with a lower risk of thromboembolism.15,16 (5) In
electrophysiology laboratories that do not utilize
general anesthesia, cryoablation leads to less
patient discomfort and lower dosing requirements
for conscious sedation when compared with
RF ablation.17,18 Thus, it can be expected that
cryoablation would result in increased procedural
tolerability as well as facilitate expedient postpro-
cedural discharge.
Practical Considerations Regarding Cryoballoon
Size
Currently, the approach to CBA is divided
into two camps, those preferring the exclusive
use of the larger 28-mm cryoballoon and those
employing a “toolbox” approach with selective
use of both the 23- and 28-mm cryoballoon. Ad-
vocates for the single large cryoballoon approach
highlight the high rate of phrenic nerve palsy
(PNP) retrospectively observed with use of a 23-
mm balloon, whereas those who advocate the
dual-balloon approach emphasize the potential for
increased long-term efficacy.7,8
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Phrenic Nerve Palsy
Described in early animal studies by Sara-
banda et al., PNP has proven to be the most fre-
quently observed complication with cryoballoon-
based ablation.5,13 A recent systematic review
summarizing the early experience with the cry-
oballoon catheter estimated that PNP occurred
after approximately 6% of clinical cryoballoon
procedures.5 Although PNP can be observed
after AF ablation regardless of the energy source
used, it occurs more frequently with balloon-
based ablation technologies when compared with
conventional catheter-based RF ablation.5
While PNP has been observed with both
23- and 28-mm cryoballoon catheters, the early
experience reported a higher rate of PNP with
the smaller 23-mm cryoballoon catheter (12.4% of
cases with the 23-mm cryoballoon vs 3.5% of cases
with the 28-mm cryoballoon).5 Early attempts to
explain the apparent disparity suggested that the
deployment of a relatively undersized cryoballoon
catheter deep inside the PV might result in an
increased risk of PNP.19 In addition to minimizing
the physical distance between the cryoballoon and
phrenic nerve, CBA at a relatively more distal
site within the right superior pulmonary vein
results in a local environment more conducive
to enhanced “cold” transfer to deeper tissue due
to less convective heating of the balloon by atrial
blood flow.5,20 As such, the “freeze” affected by a
more distal cryoballoon position can be expected
to result in a deeper penetration of cryoenergy
resulting in an increased risk of phrenic nerve
injury.
While some operators have suggested that
the incidence of PNP can be minimized through
the exclusive use of the 28-mm balloon, a
reexamination of evidence has questioned this
assertion.19,21 Although the initial high incidence
of PNP reported with 23-mm CBA is certain, it is
important to note that: (1) Monitoring for phrenic
nerve function in early studies was variable,
and not necessarily reflective of contemporary
practice; and (2) The exclusive use of larger
cryoballoon catheters has not entirely eliminated
this complication.21–24
Why Bigger Is Not Necessarily Better
Proponents for the “single big cryoballoon”
approach argue that the larger 28-mm cryoballoon
catheter facilitates a more proximal position in
the left atria resulting in the creation of an
ablation lesion that is predominantly antral in
location.21,22,25 By extension, use of the larger
diameter cryoballoon could be expected to result
in a combined reduction in the incidence of
complications associated with more distal PV
2012 3
 ANDRADE, ET AL.
Figure 2. Pictorial representation of the region of
cryoballoon to pulmonary vein (CB-PV) tissue contact
in relation to the zone of optimal cooling. Cryoballoon
catheter ablation is currently realized through the in-
jection of coolant from four equatorial jets (represented
by the X), resulting in a slightly asymmetric zone of
cooling across the face of the CB (light blue). (Panel
A) Placement of the CB catheter within a 23-mm PV
results in positioning of the region of CB-PV contact
within the zone of optimal cooling for both the smaller
and larger CB. (Panel B) Placement of the CB catheter
within a 20-mm pulmonary vein results in a more distal
positioning of the region of CB-PV contact. In the case
of a 23-mm CB, the zone of contact remains within the
zone of optimal cooling whereas the 28-mm CB results
in a more distal position predominantly outside of the
zone of optimal cooling.
ablation (i.e. PV stenosis and PNP), as well as
increased procedural efficacy owing to larger and
more proximal lesions.25
While it is true that the 28-mm cryoballoon
will result in a relatively more atrial position of
the cryoballoon catheter when compared to the
23-mm cryoballoon, the difference in the degree
of distal ablation is not as pronounced as one may
suspect, given the shape of the current-generation
cryoballoon catheter. In comparison to a sphere,
the cryoballoon catheter has a relatively more
prominent girth than height and thus more closely
resembles an onion than an orange. As such, even
though the cryoballoon-PV tissue contact point
tends to occur at a more equatorial level, the
difference in the portion of the cryoballoon that
projects distal to the left atrium-pulmonary vein
(LA-PV) junction between balloons is lessened
(Fig. 2). For example, when the PV diameter
is held constant at 20 mm, the cryoballoon-PV
tissue contact point occurs approximately 4-mm
distal to the equator with the 23-mm cryoballoon
and approximately 6-mm distal to the equator
with the 28-mm cryoballoon. In both cases,
approximately 6 mm of cryoballoon will project
distally to the LA-PV junction. In larger diameter
veins, the cryoballoon-PV tissue contact point
occurs at a more proximal equatorial position
resulting in a relatively greater degree of distal
4 2012
cryoballoon positioning irrespective of the balloon
size (approximately 8 and 10 mm with 28- and 23-
mm cryoballoon, respectively). As such, despite
the relatively greater degree of antral ablation
realized with the larger 28-mm cryoballoon, there
remains a comparable degree of distal cryoballoon
positioning regardless of the balloon size used.
Consequently, and contrary to the prevailing
viewpoint, an understanding of the biophysics
of CBA helps to explain why the incidence
of PNP has not been completely eliminated
through the use of a “single big cryoballoon”
technique. Despite the exclusive use of the
28-mm cryoballoon, some series have reported a
higher incidence of PNP than observed with the
23-mm cryoballoon.19,26 Thus, despite the more
“favorable” relationship between the cryoballoon
and PV ostia, relative “oversizing” of the cryobal-
loon within the right superior PV orifice results
in a combination of: (1) mechanical distortion
with further foreshortening of the relative distance
between the cryoballoon and phrenic nerve,
and/or (2) physical impingement of the phrenic
nerve with resultant palsy.13 Importantly, the PNP
induced by the larger cryoballoon appears to be
more severe and longer lasting than that observed
with the smaller cryoballoon.26
Given that the critical factor in preventing
PNP is avoidance of distal CBA, some authors
have suggested that this complication may be
minimized by ensuring that the diameter of
the cryoballoon catheter exceeds the diameter
of the vein. For the 28-mm cryoballoon, a
critical PV:cryoballoon ratio of 0.9 has been
suggested to avoid PNP. For the 23-mm cry-
oballoon, a PV:cryoballoon ratio of 0.8–0.85 is
proposed.8,19,26
Why Smaller Is Sometimes Smarter
From a biophysics and biomechanics perspec-
tive, there is a theoretical rationale as to why
the larger 28-mm cryoballoon may be less pow-
erful than the 23-mm cryoballoon. Although the
28-mm cryoballoon possesses a 1.5 times greater
surface area when compared to the smaller 23-mm
balloon, internal refrigerant delivery mechanisms
are identical. Thus, irrespective of cryoballoon
diameter, cryorefrigerant is delivered to the distal
end of the current-generation cryoballoon catheter
through a central injection tube at the same
rate. The measured return flow in both balloons
is of 6.2 L of vapor per minute. Thereafter,
the refrigerant is sprayed to the distal face of
the balloon through four jets positioned slightly
distal to the cryoballoon equator at 90◦ from
one another. Consequently, the smaller surface
area of the 23-mm cryoballoon results in a rel-
atively more concentrated delivery of refrigerant
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 BIOPHYSICS AND BIOMECHANICS OF CRYOBALLOON ABLATION
Figure 3. A diagrammatic representation of three
pulmonary venous (PV) anatomic variants differentially
treated with the 28-mm (above) and 23-mm (below)
cryoballoon (CB). Optimal CB-PV tissue contact is
represented by a white arrow, whereas suboptimal tissue
contact is represented by a black arrow. (Panel A)
Optimal contact is realized with both the 28- and 23-mm
CB. (Panel B) A relatively small venous caliber results in
relative externalization of the CB. When the larger CB is
used, the more proximal position results in suboptimal
tissue contact along the antral region. Conversely, the
smaller CB results in a more distal position resulting
in optimal CB-PV tissue contact along the antral region.
(Panel C) Early branching or acute PV angulation results
in asymmetric CB-PV tissue opposition. With the larger
CB, the more proximal positioning optimizes tissue
contact along one margin (in this case the superior
margin) at the expense of suboptimal contact along the
inferior margin. When the smaller CB is used, the more
axial alignment of the CB-PV axis results in a more
central venous occlusion, which optimizes CB-PV tissue
contact along the zone of optimal freezing.
(1.5 times greater per mm2 ) resulting in more
uniform cooling of the anterior aspect of the
cryoballoon catheter when compared to the larger
28-mm cryoballoon.
Therefore, the less concentrated and more
heterogeneous cooling obtained with a 28-mm
cryoballoon catheter must be weighed against the
creation of larger, more antral ablation lesions.
Indiscriminate use of a relatively oversized cry-
oballoon becomes problematic in smaller veins,
or in those with more challenging ostial geometry
(Fig. 3).25,27 In these smaller, more anatomically
challenging PVs, the combination of suboptimal
cryoballoon-PV contact with a relatively reduced
cryorefrigerant density could be expected to result
in less efficient freezing with the 28-mm balloon,
thus leading to the creation of a less homogeneous
lesion. Returning to our previous example, the
use of either cryoballoon in a 23-mm PV would
result in the cryoballoon-PV contact point within
the zone of optimal cooling, although the contact
PACE, Vol. 00
point with the 23-mm cryoballoon would be
more equatorial (Fig. 3). With smaller diameter
PVs, the contact point is pushed more distally
along the surface of the cryoballoon. While the
cryoballoon-PV contact point remains within
the zone of optimal cooling with the 23-mm
cryoballoon, the more distal position with the
28-mm cryoballoon will result in a cryoballoon-
PV contact point at the limit of the zone of optimal
cooling. Given the relatively nonuniform nature of
cooling with the larger cryoballoon, the potential
for gap formation may theoretically lead to a
reduction in procedural efficacy.
Conversely, in small PVs or those with a
more oval geometry, use of a 23-mm balloon
would result in relatively closer contact with atrial
walls surrounding the PVs and may, therefore,
translate into increased efficiency of freezing
with consequently better long-term outcomes.8,27
Indeed, this has been observed in a recent study
of 455 patients by Vogt et al.8 A strategy of PVI
that included the 23-mm cryoballoon resulted in
a significantly greater freedom from recurrent AF
over a mean follow-up 20.5 ± 15 months when
compared to PVI with the 28-mm cryoballoon
alone (78% success with the dual balloon strategy
vs 72% with the 23-mm balloon alone vs 55% with
28-mm balloon alone; P = 0.00001 for dual vs 28-
mm and P = 0.004 for 23-mm vs 28-mm).8
Similarly, Nadji et al. examined 118 patients
preselected for PVI with either the 23-mm
(29 patients with all PVs <20 mm) or 28-mm
cryoballoon (89 patients with ≥1 PV ≥20 mm).26
AF-free survival, after a mean follow-up of
Figure 4. (Panel A) Representation of the cooling zone
of the current Arctic Front cryoballoon. (Panel B)
Improved refrigerant distribution on the distal face of
the cryoballoon. (Panel C) Illustration of the resultant
cooling area with improved refrigerant distribution.
2012 5
 ANDRADE, ET AL.

Figure 5. Illustration of different PV anatomies typically encountered. Differences in PV diameter, the presence of
common ostia, the ovality of PV, as well as the angle of PV and its branches may vary greatly. A redesigned balloon
should consider such anatomical differences to ensure better balloon to tissue contact when ablating the LA-PV
junction.

19.9 ± 5 months, was similar in the two groups
(69% with the 23-mm balloon vs 62% with the
28-mm balloon; P = 0.57). Although the incidence
of PNP did not differ between groups, it is
interesting to note that despite the lower freezing
temperatures achieved with the 23-mm balloon,
all four cases of PNP resolved within 1 week.
Conversely, with the 28-mm cryoballoon, only one
of nine cases of PNP resolved within 3 months,
with five of eight recovering more than 6 months
later. Moreover, the authors noted a significant
increase in the incidence of left atrial flutter in the
group treated with the 28-mm cryoballoon (five
vs zero cases with 28-mm vs 23-mm cryoballoon;
P = 0.008).26
Future Considerations
Although the current-generation cryoballoon
catheter has shown considerable success, addi-
tional refinements in the design may potentially
further improve procedural outcomes. To this
end, there are three areas where a planned
redesign of the cryoballoon-FlexCath apparatus
may prove beneficial. Firstly, an update to the
N2 O refrigerant distribution system that allows
for more homogeneous cooling in a wider
refrigerant band would optimize lesion creation in
anatomically challenging veins, as discussed ear-
lier (Fig. 4). Secondly, given the importance of ade-
quate balloon-to-tissue contact in the attainment of
complete PV occlusion, a redesign of the steerable
sheath used with the cryoballoon (FlexCath R
,
Medtronic) to allow a greater deflection angle and
maneuverability may be beneficial. Lastly, given
the variations in left atrial anatomy encountered
during PVI (Fig. 5), a redesigned balloon with
increased conformability would enhance balloon
to tissue contact at the LA-PV junction leading to
improved lesion efficacy.

6 2012 PACE, Vol. 00

 BIOPHYSICS AND BIOMECHANICS OF CRYOBALLOON ABLATION
Conclusion
Cryothermal ablation by means of a balloon
catheter is an effective treatment for PV isolation
in patients with AF, with several theoretical
advantages compared to RF. An understanding
of the biophysics of CBA can help to inform the
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