Contemporary ReviewCryotherapy of cardiac arrhythmia: From basic science to the bedside
Introduction
The mechanism of cryoablation differs considerably from that of radiofrequency (RF) ablation.1 Tissue heating with RF energy is a result of resistive heating at the interface between the catheter and the tissue. This heating is a direct function of the current density at the catheter ablation electrode onto the myocardial interface extending a few millimeters into the tissue.2, 3 Resistive heating increases the tissue’s kinetic energy by virtue of increasing molecular movement. In contrast, cryotechnologies remove heat from tissues, lowering molecular movement and stored kinetic energy, which results in tissue cooling and ice formation.4 Blood flow and surrounding body tissues return heat to the deficit area, a potential obstacle during ablation of a highly perfused organ such as the heart.
Cryocatheters come in 2 distinct types: traditional tip ablation catheters used for focal ablation and balloon used for PV isolation. Focal cryocatheters can have 4-, 6-, and 8-mm tips and have 3 additional proximal ring electrodes allowing for electrophysiological recordings. Medtronic has 3 focal cryocatheters: Freezor (7 F, 4 mm), Freezor Xtra (7 F, 6 mm), and Freezor MAX (9 F, 8 mm). The catheter ablation tip contains an expansion chamber to produce the Joule-Thomson effect (J-T effect). In the adult patient, focal cryoablation is often used for the treatment of right-sided anterior septal accessory pathways in close proximity to the His bundle and the 4-mm tip is currently Food and Drug Administration approved for the treatment of atrioventricular nodal reentry tachycardia (AVNRT). The 6-mm tip is currently being evaluated for AVNRT treatment.
The cryoballoon catheter features an inflatable balloon that acts as the expansion chamber as the liquid nitrous oxide converts to gas. Rapid and intense cooling leads to ice formation of the tissues in contact with the balloon. It has internal thermocouples to monitor temperature within the balloon. There are 2 sizes—23- and 28-mm balloon diameters—and 2 generations—first and second. Compared to the first generation, the second generation has twice the number of refrigerant spray ports, which were moved distally to produce a more homogeneous cooling effect on the distal hemisphere of the balloon. Because of improved clinical outcomes in acute and long-term clinical studies,5, 6 an exclusive use of the second-generation balloons is recommended.
Section snippets
J-T effect
The mechanism responsible for inducing freezing in transvenous catheter ablation capitalizes on the phenomenon known as the J-T effect. At the most basic level, the J-T effect is the change in temperature of an expanding gas. In order for the J-T effect to occur, a specific set of parameters must be maintained. A liquefied gas is kept under constant pressure and insulated to prevent heat and energy exchange with the surrounding environment. This gas is passed under constant pressure from a
Direct cellular damage
The initial state of cooling—ice crystal formation intra- and extracellularly—is accelerated by nucleation. Nucleation is a physical process in which a change of state, for example, liquid to solid, occurs in a substance around certain focal points, known as nuclei. A common example is the condensation of water vapor to droplets in the atmosphere. Spontaneous nucleation occurs in cells from −5°C to −15°C.12 Nucleation begins in the extracellular space from the onset of cooling.16
Extracellular
Vascular failure
There is disagreement on whether direct cellular injury or vascular failure is the primary cause of injury from cryoablation.16 Microcirculation is damaged directly within the probe/ice ball contact area, but to a varying degree in the surrounding area. Direct cellular damage, as described above, is implicated in the distention of the vessel wall and cell death from ice formation/solute effects.11 In addition, coagulative necrosis at the ice ball site typically leads to edema that can cause
Immunological effects
Necrosis is the death of a cell due to unfavorable ionic balance, lysis, or mechanical injury. Necrosis results in spillage of internal components such as uric acid, cytokines, heat shock proteins, and DNA that are recognized as inflammatory. Released cytokines and other proinflammatory molecules stimulate aggregation of platelets, local immunological cells, and fibroblasts within hours of injury.18 Neutrophils and other granulocytes ingest cellular debris and help to clear wound areas.
Freeze/thaw cycle
Direct cellular damage is pivotal to lesion formation. The extent of scarring that yields electrically silent tissues depends on the acute damage phase, also known as the freeze/thaw cycle. The freeze/thaw cycle is composed of several key variables that each uniquely contribute to the extent of damage. These variables are cooling rate, absolute nadir temperature, duration of ablation, thaw rate/rest period, repeated cycles, and finally perfusion of the target area.
The duration of hold time is
Thaw rate
Related to duration are thaw rate and rest period. As the tissue slowly thaws, it is subject to prolonged dehydration, solute effects, and ice recrystallization. Low thaw rates are preferable to high rates. Frostbite is commonly treated using fast defrosting, and studies have shown that quickly thawing cells has a preservative effect.11 During the procedure, the optimal thawing temperature allows the natural body heat and blood flow to thaw tissues. Tissues require a few minutes to properly
Repeated cycles
Repeated cycles help ensure complete ablation. Repeating the freeze/thaw cycle has shown to extend lesion boundaries with each successive ablation, resulting in faster cooling and colder absolute temperatures.10 With subsequent freeze/thaw cycles, more cells lyse, greater microcirculatory failure occurs (reducing perfusion), and more fluid builds up. These factors improve the success of consecutive freezes. In addition, a slight displacement from the initial ablation site can act as a factor
Cardiac circulatory effects
One of the most difficult-to-assess but critical factors in cryoablation is circulatory effects. Tissues have various levels of perfusion and blood flow. Warm blood circulating across the site of ablation results in heating from convection. Capillaries and moderately sized blood vessels in tissues act as heat sources and can affect how a lesion forms. Cryoablation contends with a steady stream of blood that can markedly increase temperatures, decrease freezing rate, and speed tissue thawing.
Unique phenomenon
Cryoablation is unique to other ablation technologies with regard to 2 major properties. As the refrigerant cools, ice forms at the tissue contact site. Ice formation causes the catheter tip (or balloon) to adhere to the tissue, stabilizing it in place for the duration of freezing, which is an important factor for stable tissue contact during ablation. Another unique property of cryotechnology is cryomapping. When the tissue is cooled between 0°C and −28°C (thermocouple reading from the
Postablation healing
Within hours of ablation, a hemorrhagic area is noted at the probe site and inflammation occurs (Figure 3A). After a week, the periphery of the lesion is marked by cellular infiltrate, fibrin, and collagen stranding. In-growing capillaries begin to surround the wound. Evidence of hemorrhage and necrosis is still apparent throughout the wound site. As shown in Figure 3B, by 3 weeks the lesion is fully formed. At 6 weeks, lesions are dense with collagen, fat deposition, and surrounded by a
Esophagus
Ablation procedures in the left atrium can penetrate the thin atrial tissues and extend to adjacent structures such as the esophagus, lungs, and the phrenic nerve. A grave concern is the formation of atrial esophageal fistula. Mild to severe damage is evident within the first 10 days of ablation.35, 36, 37, 38, 39 Mild damage is characterized by superficial injury resulting from the mild degeneration of the muscular layer, myocyte straining, and mild edema. Severe damage features complete
Respiratory structures
It is possible for ablations to extend from the heart into the peripheral bronchus and lung parenchyma. One study showed that cryoablation within the PVs could extend into the parenchyma of the lungs and cause hemoptysis.42 A letter to the editor of Chest43 cited several cases in which hemoptysis occurred. The letter also mentioned that all the cases used temperatures <−55°C. This temperature is sufficient to induce cellular death, specifically necrosis. The proportion of ice at the PV was
Blood vessels
Cryoablation of large blood vessels does not induce rupture of the vessels.11 Large blood vessels can undergo necrosis, but the ultrastructure remains preserved, allowing for the continued passage of blood during healing.10 However, microvasculature may rupture, leading to hemorrhage.43 Blood in the vessel lyses during the thaw period, but clotting does not occur. Ablation results in swollen collagen fibers, necrosis, hemorrhage, and congestion of adjacent blood vessels, which can extend the
Nerves
Phrenic nerve palsy is a common complication of cryoablation. Propagation of ice from PV's can capture nerves resulting in temporary or permanent suspension of function. An early study from 194548 reported that nerves exhibit strong inflammatory responses initially from freezing damage, but have a high probability of acute or long-term regeneration, depending on the degree of freeze. A conformational study49 showed that the disruption of the myelin sheath and Schwann cell elements occurs, but
Summary
The use of cryothermy for ablative purposes is a complex process. Many factors play a role in the efficacy of lesion formation. This review is meant to improve the conceptual understanding of cryotherapy ablation and translate this knowledge to improve the clinical use of cryoablation.
Reoccurrence of conduction is possible after apparently successful ablation for multiple reasons: insufficient cryoprobe contact, insufficiently low temperature, and/or improper occlusion of the PVs. Regarding
Acknowledgments
We thank the Engineering Department of the R&D section of Medtronic and Blake Fleeman, Dr.Blake Fleeman, MD, for their editorial contributions.
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Dr Avitall is a paid consultant to Medtronic, which is currently the primary producer of cryotherapy products for electrophysiology.