On behalf of CryoCath Technologies, I want to thank EP Lab Digest for having us present on cryoablation, one of the newest energy sources to be used in the electrophysiology lab for transvenous ablation of cardiac arrhythmias. Cryoablation has been around for over 35 years in the surgical arena for the treatment of cardiac arrhythmias using a very large and stiff surgical probe. In addition, cryo has been used for over a century for the treatment of carcinoma, giving it a long history of safe and effective use in medicine. The challenge for the EP setting was getting cryotechnology into a very small, flexible transvenous catheter. About eight years ago, our engineers developed a design to get this job done. They took the idea to some prominent electrophysiologists in the Boston area, and their response was “This is really a nice idea, but it’s never going to work.” Here we are today, however, after perseverance with design and preclinical studies. In April of 2001 we started our Frosty Pivotal Trial, which was designed to evaluate the safety and effectiveness of ablating SVTs using cryotherapy in the EP lab. The patients enrolled either had AVNRT, AVRT, or refractory atrial fibrillation (AF) in which total node ablation was performed.

       During this trial, we enrolled 163 patients over about a two-year period. In the end, we were very successful in the treatment of AVNRT. Our tougher cases were in the accessory pathways and total nodes. It became obvious to us that cryoablation was different from radiofrequency ablation, and that we needed to understand cryo as an energy source a little better. In April of 2003 we were granted FDA approval for the treatment of AVNRT using our Freezor cryoablation catheter. During the first year of market release, over 60 cryoablation systems have been installed in the US.
       So how is cryo different from radiofrequency? One of the main differences is that we are not delivering heat to the tissue; rather, we are removing the heat — just like how your refrigerator or air conditioner works. By removing heat, the connective tissue matrix is not disrupted and the result is a uniform, well fibrosed lesion.
       From the outside, a cryo catheter looks very similar to a radiofrequency (RF) catheter, but on the inside their respective constructions are very different. The Freezor catheter is a 7 French (Fr) quadripolar design with 2-5-2 spacing and uni-directional deflection. We are currently working to release a second generation Freezor catheter that will be bi-directional. A thermocouple, for temperature sensing, is embedded in the gold-plated copper tip. The biggest different between a cryo and RF catheter is that the cryocatheter is a lumen catheter. Liquid nitrous oxide (N2O) refrigerant is injected under high pressure through an ultra-fine injection tube down a center lumen in the catheter. The N2O is in the liquid state until it is released into the hollow tip. When it is released into the closed tip, that is maintained under vacuum, the refrigerant and encounters a drop in pressure. The N2O then goes through a phase change from liquid to gas. As this change takes place, the heat from the tissue, that the tip is in contact with, is absorbed. The warmed vapor is then vacuumed back through an outer lumen, which is maintained under constant vacuum, and then suctioned through the hospital’s vacuum system. Because the cryocatheter is a lumen catheter, the catheter may be a little bit stiffer than what physicians are used to with a RF catheter.
       Being the patient advocate that I am and always have been as a nurse, I realized that this energy source for ablation was much safer in the heart than any heat-based energy source. The safety profile of cryoablation includes the ability to “site test” using hypothermia, cryoadhesion of the catheter to the tissue resulting in catheter stability, reduced risk of permanent AV nodal block, no perceived pain to the patient, less risk of thrombus, less risk of stenosis, and reduced risk of damage to adjacent cardiac structures.
       “Site testing” using hypothermia provides additional safety when ablating around critical structures such as the AV node/His bundle. Cell death by cryoablation doesn’t occur until temperatures of +5 C to –5 C are reached. However, hypothermic temperatures, well above the kill temperatures, will disable the electrical capability of the cell. If an undesired effect is seen such as PR prolongation, immediate warming of the tissue will result in return of baseline electrical conduction. This could be referred to as “safety site testing.” It is important to remember that a cryoablation lesion continues to grow for as much as three minutes, therefore, even if signs of heart block are not observed during the site testing mode, AV conduction must be monitored throughout the entire ablation duration. Even during ablation, the lesion leads with a hypothermic zone, causing electrical cessation but not cell death, always providing the extra degree of safety.

Figure 1A.

       Site testing using hypothermia can also be used for “efficacy testing.” The tracings in Figures 1A–1C are from the Frosty Clinical Trial, where the primary endpoints were safety and effectiveness, and a secondary endpoint was to demonstrate the transient electrical effect of hypothermia. These were from a patient with AVNRT, where a coupling interval of 500/370 reliably induced the tachycardia. Figure 1A is tachycardia induction prior to any ablation. Figure 1B is during the “site testing” mode, where the cells are chilled to test for a desired electrical effect on the slow pathway. Notice that block occurred in the slow pathway with the same coupling interval of 500/370. Figure 1C shows tachycardia induction with warming of the tissue.

Figure 1B.

Figure 1C.

       In clinical practice, the tracing in 1B would indicate that a permanent lesion delivered at this site would likely result in the desired endpoint of non-inducibility. Site testing for efficacy prevents delivering permanent ineffective ablation lesions.
       In a relative comparison of a cryo lesion volume versus an RF lesion (RF 4 mm tip 50 watts and +70 ºC for 1 minute, Cryo 4 mm tip –75 ºC for 4 minutes), they are comparable in lesion depth. However, the overall volume of the cryo lesion is almost half the volume of an RF lesion. Cryoadhesion prevents any brushing effect at the tip with the movement of the heart like you get with an RF catheter. This results in very focal and precise cryo lesions, minimizing damage to the surrounding tissue.
       Of equal importance is the histology of the lesion. Figure 2 represents a cryo lesion and an RF lesion one-week post-ablation in the canine model. In the RF lesion, the endothelial boundary is disrupted and there is evidence of thrombus formation. There is still hemorrhage present in the lesion, and fibrosis is just starting. The cryo lesion shows minimal thrombus, an intact endothelial boundary. The cryo lesion is also well demarcated and well fibrosed. **Figure2tif8385.jpg**
       Dr. Dubuc, from the Montreal Heart Institute, did a lot of our pre-clinical work with cryo. One of these studies was a thrombus comparison study, in which he delivered 45 RF lesions and 28 cryo lesions, and then evaluated them for the presence of thrombus. In the RF group, there was a 75% associated risk of thrombus. In the cryo group, there was a risk of thrombus, but it was only 13%. More importantly, the volume of thrombus with cryo was 1/10th of that with RF.
       Cryoadhesion is another advantage of cryotherapy that provides for the ultimate in catheter stability. Therefore, it allows the physician to perhaps approach an ablation differently than they normally would with RF, by ablating during tachycardia or pacing during the ablation. Abrupt changes in rhythm are not going to dislodge the catheter. This would also be an advantage if an isuprel infusion were running resulting in increased heart rate and contractility. Another added benefit of cryoadhesion is the option of reducing fluoro exposure as there is no need to check for catheter movement once the catheter is adhered. When the tissue is warmed, the catheter releases from the heart in a matter of a few seconds.
       Because of the site testing capability and cryoadhesion, there is a reduced risk of inadvertent AV nodal damage. Over 6,000 cryo cases have been performed worldwide with no reported incidence of inadvertent heart block. We have seen a lot of transient electrical effect on the AV node that reverses with warming. Figure 3 shows 2:1 AV conduction during a cryoablation for AVNRT that resolves in about eight seconds with tissue warming. Cryoablation allows the physicians to treat a group of patients that they previously couldn’t treat. Again, with the wavefront of hypothermia always leading the way and the added safety of cryoadhesion, ablation may be performed in closer proximity to the normal conduction system if necessary. Remember that the lesion peaks in about three minutes, so the patient’s rhythm must be constantly watched for signs of heart block until the freeze is completed.

Figure 3.

       The “no perceived patient pain” is another nice feature of cryoablation, especially when ablating in more sensitive regions of the heart such as the isthmus region for typical atrial flutter. This may provide the opportunity to lessen or change sedation techniques. Additionally, there is no need to dose the patients with extra sedatives prior to the ablation as some labs do when performing RF ablation.
       Other benefits of cryo include minimal risk of vein stenosis. If ablating inside the coronary sinus for posterior septal or left posterior pathways or inside the pulmonary veins for pulmonary vein isolation, there is a reduced risk of stenosis with cryo. Over the past couple of years, cryo has been widely used for pulmonary vein isolation in Europe. The results have been very encouraging, and the studies have indicated that cryo is associated with less pulmonary vein stenosis than with RF ablation. There is also reduced risk of damage to adjacent coronary arteries. There have been reported incidences of coronary infarcts from RF ablation. This is particularly enticing for the pediatric electrophysiologists working with small, thin-walled hearts.
       There is no burning or charring with cryo, minimizing the risk of thrombus and of cardiac perforation. There is minimal risk of damaging adjacent cardiac structures. There have been reported complications of left atrial/esophageal fistulas both in the EP lab and the OR, resulting in patient death. The esophagus lies just behind the left atria. Other adjacent structures include nerves and the lungs.
       We have learned from experience that the 4 mm Freezor^® catheter is not suited to treat all arrhythmias (i.e. atrial flutter and pulmonary vein isolation), as it creates a focused lesion. It is very well suited for AVNRT and treating peri-nodal accessory pathways including anteroseptal and posteroseptals arrhythmias, which lie in close proximity to the AV node. When additional cooling power and larger lesions are necessary, physicians need to choose a cryo catheter with more cooling power to create a larger and deeper lesion. CryoCath has two other focal ablation catheters — Freezor^® Xtra and Freezor^® MAX. Freezor^® Xtra has a 6 mm tip and creates lesions that are approximately 25% deeper than the 4 mm Freezor^®. This increased depth also results in lesions with larger volumes. Physicians often choose to use Freezor^® Xtra to threat accessory pathways that are further away from the cardiac conduction system. Freezor^® MAX is a 9 Fr, 8 mm tipped cryocatheter that is market released in Europe. This catheter is being used for the treatment of atrial flutter and other arrhythmias requiring deep lesions. The Arctic Circler^® CurviLinear catheter is market released in Europe, and we just completed enrollment in an IDE feasibility trial in the US for pulmonary vein isolation. A unique feature of this nitinol-based, shape retention design is when you cool nitinol, it relaxes. The Arctic Circler is positioned just inside the vein ostia and relaxes when cooled to conform to the vessel wall. The Arctic Circler Balloon catheter is a very exciting development for pulmonary vein isolation that we are currently working on. We just finished enrolling 13 of 20 patients in a European feasibility trial, and the early results are very promising. With just one or two freezes per vein, complete pulmonary vein isolation was being achieved. Hopefully, this will dramatically cut down the procedure times, making it practical for everyday use in the EP labs.
       In conclusion, I don’t believe that cryoablation in the EP lab is going to be just a flash in the pan; rather, what you’re seeing today is just the tip of the iceberg.