Cryoablation: From Techniques to Tips and Tricks

Abstract

In this chapter, readers will be able to know a better mechanism of lesion formation, the benefits of the technique for specific arrhythmias, practical uses, and tips and tricks on the procedure. The chapter will also contain the first trials that validated the technique showing recent trials comparing cryoablation of atrial fibrillation versus medical treatment. The main idea is to explore how it works for clinical cardiologists and to show electrophysiologists how to use it practically. Readers will see a comparison of cryoablation versus radiofrequency versus laser to decide which one to be used, comparing total procedure time, success rates, and clinical experience.

1. Introduction

Cryoablation is a method of destroying tissue by freezing, and it was first used for cancer treatments by Dr. James Arnott. It can be performed via surgical or percutaneous approaches. In this chapter, the focus will be on catheter ablation for cardiac arrhythmia treatments, which means percutaneous ablation.

Cryoablation causes cellular damage, death, and tissue necrosis with direct injury to cells and indirect mechanisms. Tissue cooling forms ice crystals in the extracellular space, leading to hypertonicity of this space, osmotic tension taking water from inside the cells, and dehydrating them. The intracellular membrane is altered and damage to cytoplasmic enzymes occurs but warming still can reverse this process.

When the cooling process occurs rapidly, there is no time for cellular dehydration, and free water is trapped within cells during freezing. In this scenario, there is intracellular crystal formation, which is a stage just before cellular death.

During thawing, melting ice within the extracellular space results in cell swelling and the influx of free water into the intracellular space can result in ice crystal growth, which is maximized at −20° to −25°C [1].

The rapid expansion of nitric oxide causes a decrease in the temperature of the gas (Joule–Thompson effect), which is rapidly transferred by convection and conduction to the metallic walls of the cryoprobe. The cryoprobe consists of the hollow shaft, closed electrode tip, and integrated thermocouple for the distal temperature recording. The refrigerated fluid is delivered under high pressure to the distal electrode after the fluid goes through the tip, cooling occurs to −55 to −60°C and gas is aspirated through a separate return lumen. There is also the cryoablation balloon, specific for atrial fibrillation ablation with pulmonary veins isolation [2].

By 12 weeks, small full-thickness lesions disrupt local cellularity but preserve scaffolding. Damaged cells in the center are surrounded by fibrotic scar tissue.

The advantages of cryoablation over radiofrequency (RF) are the ability to monitor the ablation zone in real-time, less painful since cooling of tissues and nerves provide an anesthetic effect, low risk of thrombus formation, and ease of use, but care must be taken when performing right pulmonary vein isolation because phrenic nerve palsy may occur. Studies have found rates ranging from 3.5% to 10% of phrenic nerve injury with most cases being transient [3].

RF uses alternating current to produce electromagnetic energy at high frequency when it passes through the small probe, gives high density, the tissue is heated directly by a resistive effect and deeper tissues are heated by conduction. Tissue within 2–3 mm from the probe is heated to 50°C–60°C, leading to coagulation and permanent cell destruction, damaging the sarcoplasmic reticulum, and irreversibly disrupting electrophysiological properties. Energy is dissipated by the convection of blood. Later, tissue is replaced by fibrin and collagen scar, and weeks more, an 8–10 mm scar remains.

Laser is another energy source recently available for cardiac ablation. It produces high-energy optical waves via an optical coupling fiber and radiating fiber tip. Power, time, and energy vary from 30 to 80W, 60–180 seconds, and from 1.5 to 9 kilojoules, respectively. Ablation occurs through controlled dielectric heating. Spectroscopic absorption of electromagnetic frequencies is converted into vibrational kinetic energy of water molecules manifested as direct heat, indirect lesions by shock waves, and blast effects that disturb myocyte elasticity. The light beam is collimated, heats the tissue without dispersion and lines are well-demarcated. Lesion length is between 2 and 5 cm, with a depth of 4 mm, and deeper lesions occur with heat conduction. At high power, laser energy causes protein denaturation and coagulation, leading to membrane destruction and loss of water. Experimentally, 30W for 180 seconds or 50W for 60 seconds can create lesions 5–7 mm deep. Excess heat can cause craters, and duration beyond 60–80 seconds, risk of perforation. Advantages are long uniform lesions during a single application with low temperature (50°C), the reduced area of ablated tissue preserves contractility, reduces the risk of thromboembolism, and minimizes perforation.

Choosing energy source must be done according to physician experience, availability of consoles, location of arrhythmias, and success rates of the technique based on multiple trials (Table 1).

	Cryoablation	Radiofrequency	Microwave	Laser	Ultrasound
Linear lesions	With linear probes	Coil-tip and pen-tip	With coil tip device	With diffusion linear tips	With serial transducers
Transmural lesion	Good	Limited (requires optimal contact)	Marginal	Excellent	Excellent (epicardial only)
Width/depth ratio	Moderate	High	Moderate	Low-moderate	Low
Duration of single ablation	Long	Moderate	Moderate	Low	Low-moderate
Endocardial application	+	+	+	+	–
Epicardial application	+	+	+	+	+
Endocardial damage	Low	Moderate	Low	Low	?
Risk for perforation	Low	Moderate	Possible at high energy	Low-high (wavelength dependent)	?
Char formation	N/A	+ (avoided with irrigation)	+	+/–	–
Flexible probe	+	+	+	+	+/–
Clinical experience	Extensive	Extensive	Moderate	Early	Early

Table 1.

Energy sources compared.

Adapted from Recent Advances in Lesion Formation for Catheter Ablation of Atrial Fibrillation Circ Arrhythm Electrophysiol. 2016;9:e003299. Different energy sources and characteristics of lesion formation, areas of application, possible complications, and clinical experience.

2. Trials for cryoablation

The first-generation cryoballoon was evaluated in the cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation [First Results of the North American Arctic Front (STOP-AF) Pivotal Trial] [4], which demonstrated an acute isolation rate of 97.6% and a relatively low rate of complications. However, long-term success rates varied from 62% with a single procedure and 77% after multiple procedures. The limitation of the first-generation balloon was a narrow zone of cooling around the equator of the balloon, the second-generation balloon has an extended cooling from the equator of the balloon to the tip, with more uniform lesions independent of balloon positioning.

A meta-analysis of 15 studies showed a success rate of 82% at 1 year in patients with paroxysmal AF and 70% in persistent AF [5]. Another meta-analysis comparing cryoablation versus radiofrequency ablation for paroxysmal AF (PAF) analyzed 16 studies including 7194 patients (2863 with cryo and 4332 with RF). There was no statistical difference between the two strategies (p = 0.159) as well as procedure-related adverse events, but procedure time was shorter with cryoablation [6].

The most impacting trial comparing these two energy sources was the FIRE and ICE Trial, with results presented in 2016. The trial compared RF ablation using a 3D mapping system with cryoablation guided by fluoroscopy in patients with paroxysmal atrial fibrillation and prior antiarrhythmic drug failure. A total of 762 patients were randomized and they found that procedure time was shorter with cryoablation but using more fluoroscopy when compared to radiofrequency. The trial conclusion was that cryoablation is non-inferior to radiofrequency when performing pulmonary vein isolation in paroxysmal atrial fibrillation in terms of efficacy and safety [7].

In 2021, Cryo-FIRST Trial [8] randomized 218 patients with paroxysmal atrial fibrillation to be treated with cryoablation as first-line therapy compared to antiarrhythmic drugs (AAD). The results were freedom from AAD after 12 months in 82.2% of subjects in the cryoballoon arm against 67.6% in the AAD arm, a 52% benefit with statistical significance (HR = 0.48, P = 0.013) (Figure 1). The conclusion was that the positive results demonstrate cryoablation being superior to AAD therapy in reducing AF recurrence in the first-line patient population.

Figure 1.

Results showing the superiority of cryoablation in atrial fibrillation compared to the antiarrhythmic drug as first-line therapy. (Adapted from Cryoballoon ablation vs. antiarrhythmic drugs: first-line therapy for patients with paroxysmal atrial fibrillation. For the CRYO-First Investigators. Europace (2021) 23, 1033–1041. doi:10.1093/europace/euab029).

Recently, the phrenic nerve injury during cryoballoon-based pulmonary vein isolation: Results of the worldwide YETI registry [9], a retrospective, multicenter, and multinational registry evaluated the incidence, characteristics, prognostic factors for phrenic nerve (PN) recovery and follow-up data during cryoablation. A total of 17356 patients underwent pulmonary vein isolation in 33 centers from 10 countries. Patients experiencing phrenic nerve injury was 4.2% (731), the mean time to occur was 127.7 ± 50.4 seconds, and the mean temperature at the time of injury was −49±8°C [9]. Recovery at 12 months was found in 97.0% (Figure 2), with only 0.06% showing symptomatic and permanent injury.

Figure 2.

Graphic showing percentual or phrenic nerve injury recovered after 12 months, and full recovery in 2 years. (Adapted from the Phrenic Nerve Injury During Cryoballoon-Based Pulmonary Vein Isolation: Results of the Worldwide YETI Registry. Circ Arrhythm Electrophysiol. 2022;15:e010516).

3. How to preform tips and tricks

Patient preparation must be as usual, with a 12-lead electrocardiogram monitoring system, vital parameters, such as heart rate, blood pressure, and oxygen saturation throughout the entire procedure, and external pads prepared, or adhesive pads put on the patient´s chest for electrical cardioversion as needed. If the procedure to be done is for supraventricular tachycardia (focal), the type of sedation can be the physician´s choice, cryoablation with a balloon can be easily performed with deep conscious sedation but, if general anesthesia is chosen, the anesthesiologist must know that curarization/neuromuscular blockade must be reversed when moving to right pulmonary vein ablation, in order not to interfere with phrenic nerve pacing/capture using a decapolar or quadripolar catheter.

For focal procedures, usually, three venous femoral access are done, one for decapolar catheter inside the coronary sinus, another for a quadripolar catheter positioned at the atrioventricular node level, capturing atrial, HIS bundle and ventricular electrograms, and the last one to be used with the cryoablation catheter, which is a 7F catheter 4 mm tipped and deflectable connected to a console and the electrophysiology (EP) system stimulator.

Ablation with a focal catheter can be performed transiently or definitely, the first one is a limited time and temperature to ensure that the chosen area isn´t going to cause any kind of damage, such as atrioventricular block (−30°C for 40–60 seconds), this technique is called cryomapping and can be divided into efficacy cryomapping when the exact site responsible for abolishing the arrhythmia is determined, or safety cryomapping when you search for unintended consequences during ablation. Definitive lesions occur at −50° to −75°C during 2–4 minutes, with the ice ball at the tip of the catheter producing good stability of the catheter. With cryomapping and good catheter adhesion, the risk of atrioventricular block for septal accessory pathways can be eliminated. The acute procedural success rate is around 84%, which is comparable to RF ablation, however, there is a high recurrence rate of approximately 29% [10].

When performing pulmonary vein isolation with cryoballoon only two venous femoral punctions can be done, one to be used with a pacing catheter (either a decapolar or quadripolar), and the other for transeptal access followed by the exchange to cryoballoon sheath. A manifold must be prepared with two connections, one for contrast injection and the other one with 1000 mL of heparinized saline in a compressed bag; another 1000 mL of heparinized saline must be prepared, with or without a second compressed bag, to be connected to the steerable sheath of the cryoballoon.

Transeptal puncture with fixed sheath (FS) must be performed according to physician’s practice, either using only fluoroscopy, or complemented by transesophageal echocardiogram (TEE) or intracardiac echocardiogram (ICE); lower transeptal puncture helps a better approach and occlusion of the right inferior pulmonary vein (RIPV), usually the most chalenge vein.

After transeptal access with FS, if one wishes to make left atrial and pulmonary veins angiography, the best way to do it is to maintain the FS at left vein ostium and, during fast ventricular pacing (400 ms), rapidly injecting contrast and recording fluoroscopy, since less amount of contrast will be needed with the first sheath. The next step is exchanging sheaths from FS to the 15F deflectable sheath (DS), which is done by preferably keeping a wire inside the left superior pulmonary vein (LSPV), while removing FS before introducing the DS, deepening the site of puncture with a small blade is needed in order to best pass through it with the sheath, which has a more robust and harder tip. When the sheath is at the transeptal orifice, viewing in left anterior oblique (LAO) projection (30° or 40°), a deflection can be done pointing toward the LSPV so the wire doesn´t come off the left side, while advancing the sheath. With the sheath inside the vein, the wire and dilator can both be retracted, the sheath flushed with heparinized saline solution, and the saline solution connected with continuous slow flushing.

Preparing the cryoballon is crucial to avoid bubbles inside the plastic cap at the tip of the catheter, two fixed sizes are available but the 28 mm is the most used. There are two “dry” connections that must be done before any flushing, one for balloon inflation and deflation with nitric oxide gas (coaxial umbilical), and a second one to capture electrical signals from the cryoConsole, such as temperature, and to energize the catheter (electrical umbilical) this latter catheter has a box in-between that decodify possible catheter or balloon errors to stop ablation and prevent injuries. The manifold and Y-shape device are connected directly to the balloon and flushed; the Y connection is flushed backward then closed and flushed forwards until the solution passes through the balloon tip. In sequence, the tip of the cryoballoon is submerged into a saline solution and its plastic cap is moved in a back-and-forth manner to completely remove air.

The last step before passing the balloon is introducing the circular multipolar diagnostic catheter (called achieve) through the Y connection until the very tip of the system, then the plastic cap is necessarily used to open the DS valve permitting the balloon to get off the sheath.

Common pulmonary vein isolation suggested sequence is LSPV, left inferior pulmonary vein (LIPV), RIPV, and right superior pulmonary vein (RSPV), because the right side is where PN injury can occur, RIPV has a greater distance to PN, pulmonary vein isolation typically precedes PN injury in RSPV, and if RIPV ablation results into PN palsy, at least three veins were already isolated. In pulmonary vein isolation, cryomapping is not usually applied and freezing until, at least, −40°C is the goal.

Ablation time began with a 4-minute freeze using the first-generation balloon in STOP-AF Trial, and in the FIRE and ICE Trial, a 4-minute bonus freeze was applied; for the second-generation balloon, a 3-minute initial ablation time has been suggested. Investigators reported an 80% success rate with 3 minutes of freezing in 143 patients in a single-arm, non-controlled study [11].

During cryoablation some parameters must be observed to ensure good vein isolation—visual fluoroscopy of vein occlusion with the balloon plus contrast injection without leaks to the left atrium (Figure 3); once you find this position the operator must maintain it until, at least 30–35 seconds of freezing, enough time to secure the system in a stable position. A good relationship between freezing time and temperature drop, which best occurs in a one-to-one fashion (e.g., −30°C at 30 seconds of freezing), graphically can be seen as a straight-line drop. Vein isolation in less than 30 seconds or 60 seconds of freezing time helps the physician to decide whether second freeze is to be performed or not, we usually take as practice one full 3 minutes ablation when isolation occurs in less or at 30 seconds, and a 2 or 3 minutes bonus freeze if isolate at or after 60 seconds.

Figure 3.

Fluoroscopy showing cryoballoon catheter occluding left inferior pulmonary, and contrast is filling the vein without leaking to the left atrium. (From the authors).

Another parameter indicating good contact and occlusion within the vein is temperature reaching −40°C between 30 to 40 seconds at a maximum of −60°C to halt freezing. A steep and rapid drop in temperature (<−40°C within 30 seconds) and nadir of the temperature of −55°C to −65°C are potential indicators that the balloon is deep inside the vein and not at an antral position, and freezing should be terminated.

There are some techniques described for ablation—the direct approach, the hockey stick approach, and alone or combined with the pull-down maneuver. If the catheter direct occludes the vein ostium, it is called the direct approach (Figure 4) and is usually good for LSPV and RSPV.

Figure 4.

Fluoroscopy showing cryoballoon catheter in a direct approach, only pushing at vein antrum, and the vein in the example is a left superior pulmonary vein. (From the authors).

The so-called hockey stick alone or in combination with a pulldown maneuver is commonly used in LIPV and RIPV. A careful PV angiogram can be used, and the most caudal branch of the inferior PV should be wired with the mapping catheter (achieve). After CB inflation, the sheath should be curved down and pushed up with the bending point at the LA roof. The CB should then be advanced to improve contact with the inferior aspect of the inferior PV, resulting in a hockey stick figure on fluoroscopy (Figure 5). If an inferior gap remains, we combine the hockey stick with a pulldown maneuver (CB and sheath) after 60 seconds. At this point in time, the CB is frozen to the superior aspect of the inferior PV and a typical response consists of an additional CB temperature drop and isolation in the next 20 seconds.

Figure 5.

Fluoroscopy showing the circular mapping catheter (achieve) in an inferior branch of the left inferior vein, and balloon and sheath in a “hockey stick” approach for better occlusion.

Before freezing right veins, PN should be paced at twice the capture threshold using a deflectable catheter, a good place for pacing is at the junction of the superior vena cava (SVC) and the right subclavian vein. Monitoring PN function can be done by direct manual palpation of the patient´s thorax or by monitoring de diaphragmatic compound motor action potential (CMAP) since the latter one alters first before PN palsy.

The CMAP is implemented using a modified ECG lead I technique. The right-arm surface ECG electrode is placed 5 cm above the xiphoid, and the left-arm surface ECG electrode is placed 16 cm from the xiphoid along the costal margin (Figure 6). Freezing is stopped in the event of a 30% reduction in the maximal diaphragmatic CMAP amplitude or any perceived reduction in the strength of diaphragmatic contraction.

Figure 6.

Positioning polygraph electrodes (12-lead electrocardiogram) with the right arm placed 5 cm above the xiphoid, and left-arm surface ECG electrode placed 16 cm from the xiphoid along the costal margin to obtain the CMAP.

4. Conclusions

Cryoablation is a feasible technique for SVT procedures with a high acute success rate, but also higher rates of recurrence compared to RF ablation; it is suggested to use it in targets where the risks of the procedure are higher than the benefits if using RF as an energy source, such as in right septal accessory pathways.

Cryoablation with a balloon catheter to treat atrial fibrillation by pulmonary vein isolation is non-inferior to RF procedure and, to date has a unique trial of superiority to antiarrhythmic drugs as first-line therapy.

Conflict of interest

The authors declare no conflict of interest.

Thanks

I would like to thank Dr. Silvia Helena Cardoso Boghossian for the first cryoballoon procedures with high expertise and patience. My thanks to Sociedade Brasileira de Arritmias Cardíacas (SOBRAC) for encouraging physicians to novel techniques by performing continuous medical education. I also thank my colleagues who helped me in writing this chapter and Dr. David C. Gaze for the opportunity of this chapter.