In this article, the authors review the science behind cryoablation, including cellular physiology and mechanism of ablation, as well as clinical applications for cryoablation such as AF ablation and ablation of certain SVTs.
The effectiveness of cryoablation is demonstrated by long-term studies from diverse clinical applications.1 Accordingly, there is a growing interest in this therapeutic option now augmented by both technological innovations that assure an ablative dose and an understanding of the pathophysiology of cell death in response to a freeze insult.
Early reports by Gallagher2-4 demonstrated successful ablation of the AV node and left posterior accessory pathways to control arrhythmias in drug-refractory patients with the added benefit of reversible cryomapping. Others reported on selective ablation for AVNRT, accessory pathways, atrial fibrillation and recurrent, sustained VT (see full reviews5,6).
Thermal Dosimetry and the Freeze-Thaw Cycle
Chilling (hypothermia) with subsequent freezing is an energy-deprivation therapy that progressively, but reversibly, reduces transmembrane ion transport, resulting in loss of the cardiac action potential. Transient cooling is fully reversible, provided temperatures are only briefly lowered to ~ -20 oC. Prolonged exposure to subfreezing temperatures is lethal, but in a strength-duration relationship for cardiomyocytes exposed to extracellular ice and absolute for cells experiencing intracellular freezing, temperatures approaching -80 oC are fully destructive.
The freeze-thaw cycle (Figure 1) defines the method of application of the “freeze insult,” and is characterized by the cryosurgical system’s capabilities and physician management, including whether to use a single or double freeze cycle. Cryosurgical systems have limitations related primarily to the type of cryogen selected (Table 1). Due to the challenge of moving cryogenic liquids (i.e., liquid nitrogen) through capillary tubing, only gaseous cryogens currently provide rapid, effective probe/catheter/balloon tip freezing. Of the available gaseous cryogens, nitrous oxide (N2O), despite its limited low temperature capability, is favored due to pressure constraints in catheter design. In the near future, cryogens such as supercritical nitrogen may provide catheter tip cooling at far more rapid rates while attaining lower ablative temperatures.
The decision on whether to use a single or double freeze cycle should be influenced by both the cryogen-type and tissue thickness. Ablation of ventricular tissue requires a double freeze-thaw cycle to assure a full thickness transmural lesion. Full thickness ablation of atrial tissue may only require a single cycle provided that appropriate nadir temperature is reached. The relative effectiveness of the freeze-thaw cycle is first dependent on the proper adhesion to the endocardial surface, which is influenced by catheter tip/balloon angle of contact. Catheter tips are most effective when contact surface between the tip and tissue are maximized. Balloons do not provide the same heat extraction capability along their entire distal curvature, so proper placement and adhesion become important. The freezing process should be allowed to proceed at as rapid a rate as possible as this allows for greater cellular damage. The “hold time” at the nadir temperature is impacted by the tip/balloon’s heat extraction capability, and therefore, extension of lethal transmural freezing. For N2O-based systems, the time to full thickness, transmural nadir temperature can exceed 4 minutes. Following the completion of a freeze, thawing is initiated. Initially, an active thaw mode is employed to provide separation between the cryoprobe tip/balloon and the endocardium. The actual thawing of the targeted tissue will be passive — a desirable feature of cryoablation since a slow thaw is more destructive.
A detailed evaluation of the events of the freeze-thaw cycle provides the basis for understanding the cumulative destructive effects of mechanical damage (ice-related) and the cellular pathophysiology resulting from the stress-induced activation of the death domain processes. Cardiomyocytes, when subject to a full freeze-thaw cycle, experience a cascade of lethal effects (Table 2). Ice forms initially in the extracellular spaces (Figure 2A). While extracellular ice is not necessarily lethal, ice formation results in the creation of a highly hyperosmotic environment (~340 mOsm to ~8,000 mOsm), a key contributor of both mechanical cell damage and initiation of apoptosis. In response to the hyperosmotic environment, cardiomyocytes will shrink as water osmoses out of the cells, followed by intracellular freezing with continued temperature decline (Figure 2B). Cell survival is further compromised during thawing, as mechanical deformation of the tissue occurs (recrystallization) followed by local anoxia and the launch of necrotic and apoptotic events.7,8
The above events occur within a clearly defined cryogenic lesion characterized by cellular devitalization and replacement with fibrous tissue. The lesion is characterized by a necrotic core corresponding to tissue volume contained within the zone of lethal temperature exposure. Local vascular disruption and capillary endothelial damage are expected, but collagen fibers persist in the fibrous stroma. Matrix architecture is maintained followed by repair processes which include lymphocyte and other mononuclear cell infiltration, the likely progression of non-inflammatory apoptosis, fibroblast migration and their differentiation into myofibroblasts. The histologic long-term outcome is a non-conducting, pliable, transmural zone of fibrosis.
Critical to future advancements is the recognition that cardiac cryoablation is a combinatorial therapeutic option. Cardiomyocytes are structurally damaged by the freezing process. Activation of the molecular-based cell death cascades (apoptosis and necrosis) is triggered by multiple factors including hyperosmotic shock, hypoxia and loss of membrane fluidity, which can be expected to occur primarily in the distal regions of the cryogenic lesion. Adjunctive approaches that utilize freeze sensitization strategies should assure even greater levels of cell death in the targeted zone. The molecular basis of cell death following cryoablation is linked to membrane or extrinsic activation of apoptosis at the lowest subfreezing temperatures, while death at milder subfreezing conditions is more dependent on mitochondrial or intrinsic apoptosis. Agents that would amplify the extrinsic apoptotic path would be expected to enhance the levels of cell death in the distal portions of the lesion, assuring precise cryoablative targeting. In cancer therapy, cryosensitizing agents include Vitamin D3 and an array of chemotherapeutic agents applied at non-toxic levels.
The clinical application of cryoablation for cardiac arrhythmias has been well described in the literature. The standard energy source for catheter ablation of supraventricular tachycardias (SVT) has been radiofrequency (RF) energy. However, a significant risk for complete heart block exists when ablating in close proximity to the atrioventricular (AV) node or His-Purkinje system. As a result, cryothermal energy is an attractive alternative energy source given its ability to impact electrical conduction at low temperatures (-20 oC to -30 oC) without causing irreversible damage to the underlying tissue. Accordingly, potential areas of interest for ablation may be cryomapped for assessment of ablation effect prior to committing to deep freezing and irreversible cellular destruction. Furthermore, the creation of an ice crystal during cryoablation results in adherence of the catheter to the underlying tissue, improving catheter stability. This is a significant advantage when attempting to ablate in unstable regions of the heart due to cardiac motion (i.e., right-sided accessory pathways along the lateral tricuspid valve annulus, left atrial appendage ridge, left ventricular papillary muscles).
Cryothermal energy has proven to be acutely as effective as standard RF energy for the treatment of atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT). It has also been successfully utilized to treat atrial and ventricular tachycardias. Typically, cryocatheters with either 4-mm, 6-mm, or 8-mm tip electrodes have been used to treat these arrhythmias. More recently, the approval of a balloon-based cryocatheter (Arctic Front® Cardiac CryoAblation system, Medtronic Inc., Minneapolis, MN) has extended the application of cryoablation to the management of atrial fibrillation.
AVNRT remains one of the most common SVTs treated with catheter ablation. The acute and long-term success rate for treating this arrhythmia with RF ablation remains high, at a cost of complete heart block in 1% of cases. De Sisti et al9 recently reviewed the literature on the acute and long-term effects of cryoablation for AVNRT versus RF energy. Pooled data from 22 studies (2,654 patients) demonstrated an acute success rate of 95% (range 85–99%) and recurrence rate of 11% (range 2–19.7%). Acute success with cryoablation parallels RF ablation; however, the recurrence rate is greater than the 3–5% recurrence rate reported with RF ablation. On the other hand, no cases of heart block requiring pacemaker implantation have been reported with cryoablation. Long-term success may improve with the use of a 6-mm (instead of 4-mm) catheter, taking advantage of a freeze-thaw-freeze cycle with each freeze being a minimum of 4 minutes, and using the complete elimination of slow-pathway conduction as an endpoint.
Ablation of paraseptal accessory pathways is frequently difficult due to close proximity to the AV node or His-Purkinje system. Once again, cryoablation with cryomapping has been successfully employed in these high-risk patients. Bastani et al10 were able to show an acute procedural success of 96% comparable to RF ablation; however, 27% of patients had recurrence. In those patients opting for a second ablation, no further long-term recurrence was noted. Furthermore, Drago et al11 have suggested that recurrence (15% in their trial) may be related to “time-to-effect” as it relates to the time interval between initiating cryomapping and demonstrating disappearance of accessory pathway conduction. A time-to-effect within 8 seconds of initiating cryoablation resulted in no recurrence, whereas time-to-effect >10 seconds resulted in a higher recurrence rate.
In a separate study, Bastani et al12 confirmed the safety and efficacy of cryoablation in treating focal atrial tachycardias originating in high-risk locations including the sinoatrial junction, parahisian, or lateral right atrium adjacent to the phrenic nerve. Twenty-five of 26 patients were successfully ablated (96%) with 3 late recurrences (12%). Repeat procedures in two of these patients resulted in complete success. No persistent heart block or sinus node dysfunction was noted. One patient had transient phrenic nerve injury that resolved within 24 hours, and another patient had persistent phrenic nerve palsy that resolved after 5 months without clinical sequelae.
Recently, the application of cryothermal energy via a balloon-based minimally invasive approach to treat paroxysmal atrial fibrillation has renewed interest in cryoablation. A balloon-based platform allows the delivery of cryothermal energy circumferentially around the ostium/antrum of the pulmonary vein. The Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP AF)13 trial served as the primary basis for FDA approval of Medtronic’s Arctic Front® Cardiac CryoAblation system. The trial demonstrated 60% freedom from recurrent atrial fibrillation in 12 months with a single procedure. Freedom from AF improved to 69.9% in 12 months, including patients who underwent a second procedure. The Continued Access Protocol (CAP AF) with >15,000 patients has shown improvement in major complications. The incidence of phrenic nerve injury decreased from 11.2 to 4.8%, and pulmonary vein stenosis decreased from 3.1 to 1.3%. Advantages of the current system are the need for a single transseptal puncture and decreased procedure times in many instances in comparison to pulmonary vein antral ablation via standard RF catheters. The FreezeAF trial14 will attempt to establish whether the cryoballoon is non-inferior to open-irrigated focal RF ablation for paroxysmal atrial fibrillation. Currently, the initial experience with the cryoballoon is favorable and the long-term efficacy of cryoballoon ablation for paroxysmal atrial fibrillation remains to be seen.
In summary, cryoablation remains an attractive alternative to standard RF energy in the ablation of cardiac arrhythmias, especially those originating in high-risk locations. The homogeneity of the cryolesion allows for maintenance of the tissue architecture, resulting in minimal disruption of surrounding vasculature outside the lesion. Endothelial integrity minimizes risk of thrombus formation and theoretically reduces the risk of stroke. Cryoablation should be considered for patients requiring ablation in high-risk anatomical locations which may result in heart block, damage to the sinoatrial node, or phrenic nerve injury. An additional consideration is the need for catheter stability. Cryoablation can also be considered in the management of medically-refractory paroxysmal atrial fibrillation.
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- Drago F, Russo MS, Silvetti MS, et al. ‘Time to effect’ during cryomapping: A parameter related to the long-term success of accessory pathways cryoablation in children. Europace 2009;11:630-634.
- Bastani H, Insulander P, Schwieler J, et al. Safety and efficacy of cryoablation of atrial tachycardia with high risk of ablation-related injuries. Europace 2009;11:625-629.
- Medtronic Inc., Arctic Front cardiac cryoablation catheter clinical reports, in support of FDA premarket approval.
- Luik A, Merkel M, Hoeren D, et al. Rationale and design of the FreezeAF trial: A randomized controlled noninferiority trial comparing isolation of the pulmonary veins with the cryoballoon catheter versus open irrigated radiofrequency ablation in patients with paroxysmal atrial fibrillation. Am Heart J 2010;159: 555–560.