Cryoballoon Catheter Ablation in Atrial Fibrillation

Pulmonary vein isolation with catheter ablation is an effective treatment in patients with symptomatic atrial fibrillation refractory or intolerant to antiarrhythmic medications. The cryoballoon catheter was recently approved for this procedure. In this paper, the basics of cryothermal energy ablation are reviewed including its ability of creating homogenous lesion formation, minimal destruction to surrounding vasculature, preserved tissue integrity, and lower risk of thrombus formation. Also summarized here are the publications describing the clinical experience with the cryoballoon catheter ablation in both paroxysmal and persistent atrial fibrillation, its safety and efficacy, and discussions on the technical aspect of the cryoballoon ablation procedure.


Introduction
Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, increasing in prevalence with age [1]. Pulmonary vein (PV) isolation with catheter ablation is one of the primary treatments for symptomatic AF refractory or intolerant to antiarrhythmic medications [1]. In some cases, it may be even appropriate to perform AF ablation as first-line therapy, particularly in selected symptomatic patients with heart failure and/or reduced left ventricular ejection fraction [2]. The main goal in catheter ablation is complete electrical isolation of the PVs, and therefore the success of the procedure and the reduction of procedurerelated complications require careful identification of the PV ostia and application of ablation to the PV antra.
Currently radiofrequency (RF) energy is the most commonly used energy source for ablation. Many studies demonstrated the efficacy of RF energy for the treatment of AF. However, this form of energy is associated with various complications including thromboembolic events, PV stenosis, and atrio-esophageal fistula [3]. Thus, new energy sources have been investigated for the treatment of AF. These include cryothermal energy, ultrasound, and laser [4].
Recent clinical and preclinical studies demonstrated that the cryothermal energy application using a balloon catheter for PV isolation is an effective treatment for AF [5,6].
The purpose of this paper is to review the current literature for better understanding of the utility of cryoablation for the treatment of patients with AF. The literature was searched in PubMed from 1950 to February 2011 with the keywords "atrial fibrillation," "cryosurgery," and "catheter ablation" published in English. A total of 100 references were found. All full-text articles and their references were reviewed and included in this paper if they were relevant to our presentation.

Effects of Cryothermal Energy at the Cellular Level
Cryothermal energy causes progressive necrosis in the absence of significant alteration of tissue structure at thaw. The effect of ablation on the cellular ultrastructure has been evaluated in studies using a cryoprobe cooled to −60 • C with expanding nitrous oxide [7]. Ice crystals were observed to form inside the cells during ablation, with a resulting cell damage that is osmotic rather than mechanical [7]. Microcirculatory changes have also been described leading to tissue necrosis. Acute changes in subcellular organelle structure and mitochondrial destruction occur in 1 minute at −70 • C. The mitochondria appear enlarged, with decreased matrix density and disrupted cristae. Striking depletion of glycogen stores takes place within 1 hour of thaw. Subsequent changes up to 10 hours after thaw are most notable for progressive mitochondrial damage. Then, the hemorrhagic and inflammatory phase starts and results in fibrosis. The cryothermal energy lesion formation can be divided in three sequential stages which are the freeze/thaw phase, the hemorrhagicinflammatory phase, and the replacement fibrosis phase. The resulting lesions are minimally thrombogenic, have sharp well-demarcated margins, and exhibit minimal tissue disruption and preserved basic underlying tissue architecture [8,9]. Thus the histopathologic changes of cryoablation are likely to be associated with low arrhythmogenic potential.

Clinical Application of Cryoablation
Cryothermal energy has been used in treatment of cardiac arrhythmias for the past 3 decades, especially in supraventricular arrhythmias. Cryoablation was performed as early as 1977 to the atrioventricular (AV) conduction system [10]. Harrison et al. studied cryoablation using a handheld nitrous oxide-cooled cryogenic probe in 20 dogs and subsequently in three patients with drug-resistant, lifethreatening supraventricular tachycardias [10]. In the same year accessory pathway elimination by cryoablation was demonstrated by Gallagher et al. [11]. Since then, numerous experimental and clinical studies have evaluated the efficacy and safety of cryoablation [4,5,9,[12][13][14]. A multicenter clinical trial in patients with AV nodal reentry tachycardia (103 patients), AV reentrant tachycardia (51 patients), and AF (12 patients) demonstrated that cryoablation is a safe and effective strategy for the treatment of supraventricular arrhythmias [12]. Catheterbased cryoablation was found to be a safe alternative to RF ablation for slow pathway modification, accessory pathway termination, and AV junction ablation. Acute procedural success was achieved in 83% of the overall group, and long-term success after 6 months was 91%. Cryomapping (cooling the catheter tip to −30 • C) successfully identified ablation targets in the majority of the patients, and the electrophysiologic effects of cryomapping were reversible within minutes in 94% of the attempts.
Also, a prospective, randomized trial in patients with recurrent narrow QRS-complex tachycardia suggestive of AV nodal reentry tachycardia compared cryoablation with RF ablation and showed a procedural success rate of 91% in the RF group and 93% in the cryoablation group [13]. The median number of cryothermal applications was significantly lower than the number of RF applications. Both fluoroscopy and procedural times were comparable. No cryoenergy-related complications were observed, and no permanent AV conduction block occurred. Long-term clinical success was comparable in both groups.
Currently cryoablation is used to treat various forms of ventricular and supraventricular arrhythmias including AV nodal reentry tachycardia, AV reentrant tachycardia, atrial flutter, and focal atrial tachycardia [12][13][14][15][16][17][18]. Compared to RF ablation, cryoablation has been associated with lack of pain during energy delivery, homogenous lesion formation, less destruction to surrounding vasculature, preserved tissue integrity, and lower risk of thrombus formation [5][6][7][8][9][12][13][14]. Lesion reversibility is another advantage of cryoablation over RF energy and is useful for ablation of accessory pathways in proximity to the conduction system [12][13][14][15]. Moreover, cryoablation can be applied within venous structures, like the coronary sinus and the middle cardiac vein with less risk of thrombosis compared to RF ablation [14,19]. It has been shown that cryoablation in the coronary sinus within 2 mm of the left circumflex artery produces myocardial lesions similar to RF ablation with lower risk of coronary artery stenosis [19].
The absence of endothelial disruption with cryoablation results in less thrombogenicity and may offer an opportunity for improved safety during ablations in the left side of the heart [5][6][7][8][9]. This may be important when large areas of the endocardium are ablated such as in AF ablation procedures. All these characteristics of cryoenergy, in addition to the ability to use it with a balloon, make it an attractive source of energy for PV isolation.

Balloon-Based Ablation Catheter
Point-to-point ablation using a focal catheter for PV isolation is associated with technical difficulties and requires experienced operators with high level of skills. Pulmonary vein isolation using a focal cryocatheter has been studied and was found to be associated with long procedure times [20]. The cryoballoon catheter was designed with the aim of facilitating PV isolation [4][5][6]21].

Ablation Technique.
Currently only one balloon design is available for clinical use (Medtronic Inc, Minnesota, Minn). This system includes an over-the-wire balloon catheter which is cooled using nitrous oxide (N 2 O) [4][5][6][22][23][24][25][26][27]. The balloon shaft size is 10.5 F and has a deflection mechanism. It is introduced into the left atrium using a 14 Fr steerable sheath. The shaft has a central lumen that can accommodate a wire for support and also used for contrast and saline injection.
The wire is used to engage the vein first. The balloon is inflated outside the vein and advanced over the wire to occlude the vein (Figure 1). Obtaining a complete occlusion is crucial for successful isolation. An incomplete occlusion will lead to flow around the balloon and prevents the temperature from reaching low enough levels necessary for adequate ablation. A complete occlusion is typically confirmed by injecting contrast in the lumen at the balloon tip. Once occlusion is confirmed, the contrast is flushed using saline and freezing is started. If successful, a dip in the temperature curve is observed indicating a better occlusion. Lesions are usually 240-300 sec long and PV isolation is usually achieved with one lesion in most patients [22][23][24]. Most operators apply one additional lesion after isolation.
Currently, two sizes of the cryoballoon catheter are available, 28 mm and 23 mm diameter. It is advisable to use a 28 mm balloon regardless of the size of the vein in order to reduce the risk of complications such as PV stenosis and phrenic nerve injury. A quadripolar catheter is usually positioned in the superior vena cava for continuous  Figure 2). Recently, the use of transesophageal echocardiography with color Doppler was described allowing real-time visualization of the cryoballoon during ablation [28].
After ablation, PV isolation is assessed using a circular mapping catheter inserted in the left atrium via a separate transseptal puncture [22,25,29]. A small caliber circular mapping that can be advanced in the central lumen instead of the wire can also be used to confirm isolation.
In some patients technical challenges can be encountered leading to the inability to obtain a complete occlusion. Two maneuvers can be helpful if complete occlusion cannot be achieved by advancing the balloon. The first involves trying to engage a different branch with the wire. This can provide a better alignment of the catheter shaft with the axis of the PV. The second maneuver is the "pull-down" technique [24]. This can be useful when a gap is present at the inferior border of the vein and cannot be closed despite advancing the balloon. With this technique, freezing is started despite the presence of the gap. At about 60-90 sec into the freeze, the balloon and the sheath are both pulled down gently in order to close the gap at the inferior portion of the vein. This should be done very carefully because of the risk of severe vascular damage if excessive force is applied. If occlusion and isolation cannot be obtained despite these maneuvers, a standard point-by-point ablation catheter can be used for completion.
The sites of PV reconnection have been analyzed in some studies [24,[29][30][31]. The inferior border of the veins as well as the ridge between the left atrial appendage and the left PV was found to be the sites where most reconnections occurred. This is likely to be the result of sharp catheter angulation with loss of central cryoballoon alignment with the axis of the PVs.
An early report by Van Belle and colleagues described 57 consecutive patients with paroxysmal AF who underwent cryoballoon ablation [22]. Eighty-four percent of the targeted PVs were successfully isolated using the cryoballoon and the rest required a standard cryocatheter to achieve isolation. A daily monitoring of rhythm demonstrated a significant reduction in AF burden. Klein et al. reported the result of cryoballoon ablation in 21 patients with symptomatic paroxysmal AF in 2008 [26]. A total of 95% of PVs were isolated, and 86% of the patients remained free of AF after 6 months based on periodic holter monitoring. Subsequently, Neumann et al. evaluated the efficacy of cryoballoon ablation in 293 patients with paroxysmal and 53 patients with persistent AF [23]. Ninety-seven percent of the PVs were isolated with either cryoballoon alone or in combination with a standard cryocatheter. Maintenance of sinus rhythm was reported in 74% and 42% of the patients with paroxysmal and persistent AF, respectively. In a recent study by Ahmed et al. [24], the permanence of PV isolation after cryoballoon ablation was tested in 12 patients with paroxysmal AF. Eighty-eight percent of PVs remained isolated at 8-12 weeks after the initial procedure.
The most comprehensive result regarding the efficacy and safety of the cryoballoon catheter ablation for the treatment of AF was obtained from the STOP-AF trial [32,33]. This trial randomized patients with paroxysmal drug-refractory AF in a 2 : 1 fashion to either PV isolation with cryoballoon ablation or antiarrhythmic drug therapy. Balloon-only isolation of PVs was achieved in 90.8%, and the overall procedural success (≥3 PVs isolated) was achieved in 98.2% of the patients. Nineteen percent of the patients needed a repeat cryoablation procedure within the 90-day blanking period. The success rate at 12-month followup was 69.9%.
The use of cryoballoon for PV isolation in patients with persistent AF has been associated with high rates of arrhythmia recurrence [23,34,35]. This is not surprising knowing that the left atrial substrate and not only the PVs play a role in AF maintenance in this subgroup of patients. A study from our group investigated the combined use of cryoballoon PV isolation and conventional RF ablation of areas of complex fractionated electrograms in 22 patients with persistent AF [27]. After a single procedure, 86% of patients were AF-free at 6-month followup.
In this study the followup was performed in most patients using implantable loop monitors allowing automatic detection of asymptomatic AF. In addition to AFfree survival, AF burden reduction was also analyzed in some studies. Van Belle et al. studied 144 patients with symptomatic AF refractory to antiarrhythmic drugs who underwent cryoballoon PV isolation [36]. Followup was performed using daily transtelephonic ECG monitoring, 24 h Holter-ECG, and an arrhythmia-focused questionnaire to document AF. After ablation, AF burden was reduced from 26% to 9%.
Another important procedural complication with the cryoballoon is PV stenosis. Although earlier studies showed no significant incidence of PV stenosis following cryoballoon ablation, STOP-AF trial demonstrated 3.1% risk of PV stenosis in its study population [32,33]. This complication is likely associated with ablation of the tubular portion of the vein. As a result, it is believed that the use of the 28 mm balloon can reduce this complication because this larger balloon is less likely to be positioned inside the vein during ablation [25]. For the same reason, it is believed that the use of the larger balloon will carry a lower risk of PNP.
There are no reports of atrioesophageal fistula associated with the use of the cryoballoon. The effect of cryoballoon PV isolation on the esophagus has been studied [37]. Luminal esophageal temperature was significantly decreased (>1 degrees C) in 62 of 67 (93%) patients, and reversible esophageal injuries were seen in 17% of patients. However, no atrial-esophageal fistula was documented and the followup endoscopy confirmed healing of all ulcers.

Comparison with Conventional Radiofrequency Catheter
Ablation. Both conventional focal RF ablation and cryoablation are used for PV isolation and both are shown to be effective [1][2][3]. Recent studies compared clinical outcome of cryoballoon ablation for PV isolation with RF ablation in regards to the safety and the efficacy of the procedure [30,35,42].
Linhart et al. demonstrated in a case-control study of 40 patients with paroxysmal atrial fibrillation that cryoballoon ablation has similar success rate to RF ablation in addition to similar procedure and fluoroscopy times [42]. Kojodjojo et al. studied the efficacy of a strategy using a large cryoballoon to perform antral PV isolation in 124 patients with paroxysmal and persistent AF [35] and compared it with RF ablation. At one-year followup, 77% of paroxysmal and 48% of persistent AF patients remained free from AF after a single procedure. In the RF group 72% of the patients with paroxysmal remained free of AF. The procedural and fluoroscopic times with cryoablation were shorter than RF ablation. A recent study from Kühne at al. confirmed the shorter procedure duration with cryoablation compared to RF (166 ± 32 versus 197 ± 52 minutes) [30]. In this study, a total of 55 patients with paroxysmal AF were studied: 25 patients underwent PVI using a 28-mm cryoballoon and 25 patients using an open-irrigation RF catheter. The number of procedures was not different in the 2 groups (1.2 ± 0.4 in cryoablation versus 1.3 ± 0.6 in RF ablation) with a success rate at one-year followup of 88% in the cryoballoon group and 92% in the RF group. Another study, the Freeze AF trial, is being planned to compare cryoballoon catheter ablation with open-irrigation RF ablation in a randomized clinical study including 244 patients with paroxysmal AF [43].

Conclusions
Cryoballoon catheter ablation is a safe and effective technique for PV isolation to treat paroxysmal AF. Overall success rate in persistent AF is lower. Potential procedural complications related to cryoballoon ablation include PNP and PV stenosis as well as rare neurological complications.