Key Points
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Cryolesions are smaller and show less thrombus than radiofrequency (RF) lesions when a similar tip size is used.
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Cryomapping is possible only at −30°C; deeper temperatures cause persistent damage.
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Acute results are comparable with both techniques; atrioventricular nodal reentry tachycardia (AVNRT) can be effectively and safely ablated with cryoenergy.
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Collateral damage such as permanent atrioventricular (AV) block is nonexistent with cryoablation and 4-mm tips, if mapping at −30°C is performed before ablation.
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Long-term results of cryoablation in AVNRT are as good as RF results.
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Cryoablation allows a safe approach in noninducible patients.
Ablation for atrioventricular nodal reentry tachycardia (AVNRT) is very effective; however, it has the potential for damage to the conduction system. This may occur during the procedure but also late, even years after the procedure. Cryoablation offers an alternative because it allows cryomapping, which permits assessment of slow pathway elimination at innocent (less low) freezing temperatures, avoiding permanent damage. We have reassessed this feature in animals and present an overview of acute results in comparative trials, which also studied different approaches of cryoenergy delivery, together with our own long-term data on efficacy of cryoablation.
Atrioventricular Nodal Reentry Tachycardia
The most common regular supraventricular arrhythmia in otherwise healthy young people is AVNRT. Its substrate is well studied and typically is composed of two pathways over the atrioventricular (AV) node, creating the possibility of a circus movement in a small region in the triangle of Koch and the AV node. One of the pathways is the fast pathway, which (for the typical form) acts as the retrograde limb during tachycardia. The other one is the slow pathway, which is the antegrade limb during paroxysms ( Figure 11–1 ). The arrhythmia is typically provoked by atrial or ventricular extrasystoles, making one pathway refractory when the next impulse arrives, enhancing conduction through the other pathway, and closing the circle. During this tachycardia, the P wave is negative in leads II, III, and aVF and positive in V 1 , as the atrium is depolarized from the AV nodal (septal) region simultaneously toward the right and left atria. The retrograde P wave is, therefore, narrower than the normal P wave, and is often integrated in the QRS complex, or immediately follows the QRS (even mimicking right bundle branch block [RBBB] in V 1 ). The atypical form is less common, with retrograde conduction over the slow pathway and antegrade conduction over the fast pathway. The P wave then comes late in the RR interval, with a PR interval shorter than the RP interval. The negative P wave in II, II, and aVF is seen in front of the QRS complex. The slow pathway is not a well-described structure and can have multiple components, making ablation not always easy. Although drug therapy of both forms of AVNRT was aimed at slowing AV conduction, ablation is currently directed at interruption of conduction in the slow pathway.
Catheter Ablation
After a short era of surgical correction of the substrate in specialized centers, radiofrequency (RF) catheter ablation was introduced. It is a highly effective technique with a success rate of about 95% and a low recurrence rate. Ablation is guided by anatomic landmarks and intracardiac electrograms (fractionated low-amplitude atrial signals and a low ratio of the atrial vs. the ventricular signal in the region of interest). Searching for slow pathway potentials is another approach, but ablation of such electrograms was never associated with success. A typical phenomenon, but not an end point of RF ablation, is accelerated junctional rhythm during application. If slow pathway conduction is abolished after application, there is retrospective proof that the target was successfully eliminated. The integrity of AV conduction should be assessed throughout the application, whenever feasible. This is not always easy, certainly when junctional rhythms arise. Ventriculoatrial (VA) block, in contrast, is predictive for long-term success. The real proof of successful ablation is noninducibility.
Unfortunately, there are no means to prospectively identify the right spot with RF. Assessment of AV conduction after applications may reveal that irreversible damage is created. Importantly, there is an increased risk for right bundle branch block or inadvertent complete heart block with RF in all registries. It is thought to happen infrequently, but as some variations in anatomy and physiology are present, it is still bound to happen in every large series.
Therefore, alternative approaches were investigated, of which cryothermy, well-known to most surgeons with an interest in the treatment of cardiac arrhythmias, became the most successful one. After our initial randomized trial, we remain convinced it is a standard therapy for AVNRT. This chapter analyzes experimental and clinical data to support this hypothesis.
Experimental Data
Cryothermal energy has the advantage that it can be used to demonstrate reversible loss of tissue function by cooling tissue at moderately deep temperatures (−30°) to assess the suitability of prospective ablation sites without permanent injury. Some work was done in this respect by Dubuc. Usually, mapping attempts at −30°C are made before freezing to −70°C. Some authors proceed now immediately to real freezing, for a short time, in an attempt to determine whether they are at the right site. However, it is not known whether such freeze/thaw cycles are completely safe for structures of vital importance such as the AV node and whether more effective temperatures such as −40°C are equally safe for mapping. We undertook an animal study to understand the impact of short (60-second) and long (240-second) applications at −30°C and −40°C, in comparison with long applications at −70°C and RF energy (60 seconds).
Materials and Methods
The experiments were performed in normal crossbred Landrace–Yorkshire pigs (±35 kg), complying to the regulations of the animal care committee of Erasmus University Rotterdam and the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication No. 85-23). After antibiotic prophylaxis, anesthesia with 10 to 15 mg/kg thiopental, and endotracheal intubation, the pigs were ventilated and administered a mixture of oxygen and nitrous oxide. Isoflurane was given for anesthetic maintenance. The bundle of His was targeted after femoral vein cannulation with a 4-mm tip catheter (either Freezor or CryoCath for cryoenergy, or Helios or Stereotaxis for RF). For cryoenergy, mapping was performed for 60 seconds, at −30°C or −40°C. Cryoablation was attempted for 240 seconds at −40°C or −70°C. RF ablation was performed for 60 seconds, with a setting aimed at 45°C and 50 watts. Procedures were terminated when temporary or persistent heart block occurred.
After a follow-up period of 3 days, the AV conduction was assessed by comparing the 3-day and the baseline PR interval. The heart was assessed macroscopically, and sections were stained with hematoxylin and eosin and resorcin-fuchsin for histologic analysis. Calcifications were confirmed by von Kossa staining. Morphometric analysis of the lesions was performed using a microscopy image analysis system (Impak C, Clemex vision image analysis system; Clemex Technologies, Longeuil, Quebec, Canada). For statistical analysis, all data are given as mean ± standard deviation. Nonparametric tests were used when appropriate. P < 0.05 was considered statistically significant. A one-way analysis of variance (ANOVA) test was performed in the three groups with ablation to understand trends in lesion formation and characteristics versus the applied energy modality.
Results
Electrophysiology
The results of the 19 studied animals are summarized in Table 11–1 . Cryomapping at −30°C induced first-degree heart block in one animal. At day 3, none had PR prolongation. Cryomapping (60 seconds) at −40°C yielded an acute AV conduction disturbance in two of three cases that had completely disappeared at day 3. Cryoablation (240 seconds) at −30°C showed no effect at all. Cryoablation at −40°C gave electrocardiographic effects in two of three animals ( Figure 11–2 ), persisting until death. One other animal developed VF (without preceding heart block) and could not be resuscitated. Of the four animals with cryoablation at −70°C, three had electrocardiographic evidence of acute effects ( Figure 11–3 ). The AV conduction disturbances persisted until the time of death (see Figure 10–3 C ). All four animals treated with RF ablation had heart block. At death, three still showed heart block, and one had bradycardia with a wide escape rhythm and 1 : 1 VA conduction.
| ELECTROPHYSIOLOGIC ASSESSMENT | HISTOLOGIC ASSESSMENT | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| GROUP | DURATION (sec) | N * | ACUTE EFFECT | EFFECT AT DAY 3 | THROMBI | LESIONS | DISCREET INFLAMMAMATION | INTENSE INFLAMMAMATION | NECROSIS | CALCIFICATION |
| CRYOMAPPING | ||||||||||
| −30VC | 60 | 3 | 1/3 | 0/3 | 0/3 | 1/3 | 0/3 | 1/3 | 0/3 | 0/3 |
| −40°C | 60 | 3 | 2/3 | 0/3 | 0/3 | 2/3 | 2/3 | 0/3 | 0/3 | 0/3 |
| CRYOABLATION | ||||||||||
| −30°C | 240 | 1 | 0/1 | 0/1 | 0/1 | 0/1 | 0/1 | 0/1 | 0/1 | 0/1 |
| −40°C | 240 | 4 | 3/4 | 1/3 † | 1/3 | 2/3 | 2/3 | 0/3 | 1/3 | 1/3 |
| −70°C | 240 | 4 | 3/4 | 3/4 | 2/4 | 4/4 | 1/4 | 3/4 | 4/4 | 3/4 |
| RADIOFREQUENCY | ||||||||||
| 45°C | 60 | 4 | 4/4 | 4/4 ‡ | 2/4 | 3/4 | 0/4 | 3/4 | 3/4 | 2/4 |
* Animal studies; the number of animals is given.
† One animal had ventricular fibrillation.
Histology
Cryomapping at −30°C showed, in one case, a discrete lesion at the AV junction; ablation at −30°C showed no lasting effects at day 3. Cryomapping at −40°C yielded a visible, discrete lesion at day 3 without necrosis in two cases ( Figure 11–4 ). Cryoablation at −40°C showed discrete lesions in two of three animals, one with necrosis and calcification. Only one thin luminal thrombus was observed.
Cryoablation at −70°C showed macroscopically clearly demarcated lesions ( Figure 11–5 ), with histologically patchy necrosis and calcification, surrounded by intense inflammatory infiltrates. A thin luminal thrombus was observed in two pigs.
In general, intense inflammation became more evident with increasing energy intensity ( P < 0.10). No other trends were observed. RF lesions could easily be identified in three of four animals. A consistent massive area of necrosis and calcification was seen in three and two pigs, respectively, surrounded by intense inflammatory infiltrates. More importantly, large platelet-rich thrombi at the RF ablation site were found in two animals ( Figure 11–6 ).
Conclusion of the Experimental Data
This study clearly confirms that short cryomapping at −30°C and −40°C is not associated with long-lasting electrophysiologic effects, and certainly not with specific persistent microscopic lesions such as necrosis. However, discrete inflammation was observed with short applications of −40°C. This is not surprising, as often multiple attempts were made to identify a site of interest, as sometimes is the case in clinical practice. Longer applications (240 seconds) carry a greater risk for permanent damage (already at −40°C) and are associated with persistent electrocardiographic effects. Histology showed that only at −70°C do lesion characteristics take on the aspect that can be expected from tissue ablation: necrosis and calcification. RF ablation showed larger lesions and was more effective in this animal model. Large, platelet-rich thrombi were seen only in the RF group. Cryoenergy was never associated with large adherent thrombi.
Acute Results of Cryoablation in Humans
Procedural Outcome
The acute effect of cryoablation is comparable with the outcome of ablation with RF, certainly when the only two randomized trials are considered. From a statistical point of view, the acute procedural result is not different from RF. The difference is 95% (cryo) versus 97% (RF) for all comparative trials ( Table 11–2 ). The real efficacy should be the long-term outcome. The randomized trials showed 8% (cryo) versus 3% (RF) recurrence, over a rather short follow-up period (8 and 13 months). If all the trials are combined, the failure rates are 9.8% versus 4.5%, in the advantage of RF. There are some outliers with a very high failure rate, which also is demonstrated in the observational trials, as shown in Table 11–3 . Part of it might be because of a learning curve. Furthermore, this is confused by the sequential, not randomized, use of 4-mm and only later 6-mm tips. Some of the “failed” patients will remain symptom free, as is the case after “failed” RF. Other patients effectively require a second procedure. Analyzing our long-term data (follow-up, 4 ± 2.4 years), we see that the number of redo procedures in the RF approaches 6.5%, compared with 7.5% for cryotherapy, which is similar for both techniques.
