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CONTEMPORARY REVIEW
Cryotherapy of cardiac arrhythmia: From basic science to the bedside Boaz Avitall, MD, PhD, FHRS, Arthur Kalinski, BS From the University of Illinois at Chicago, Chicago, Illinois. This review focuses on the basic science of cellular destruction by tissue freezing and application to treat cardiac arrhythmia with the use of transvenous cryocatheter technology. Ideally, foci for arrhythmias are selectively ablated, arrhythmogenic tissues are destroyed, and reentry circuits are bisected in order to silence adverse electrical activity, with the goal of restoring normal sinus rhythm. The mechanism of ablation using cryotherapy results in distinct lesion qualities advantageous to radiofrequency (Khairy P, Chauvet M, Lehman J, et al. Lower incidence of thrombus formation with cryoenergy versus radiofrequency catheter ablation. Circulation 2003;107:2045–2050). This review is devoted to the mechanism of cryoablation, postablation histopathological changes, and
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 8mm 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 JouleThomson effect (J-T effect). In the adult patient, focal
Address reprint requests and correspondence: Dr Boaz Avitall, University of Illinois at Chicago, 840 S Wood St, Suite 922, Chicago, IL 60612. E-mail address: [email protected]. Dr Avitall is a paid consultant to Medtronic, which is currently the primary producer of cryotherapy products for electrophysiology.
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
how this information should be used by the clinicians to improve safety and maximize ablation success. KEYWORDS Cryoablation; Pulmonary vein isolation; Arrhythmia; Cryoballoon ABBREVIATIONS AVNRT ¼ atrioventricular nodal reentry tachycardia; J-T effect ¼ Joule-Thomson effect; PV ¼ pulmonary vein; RF ¼ radiofrequency (Heart Rhythm 2015;0:-3–9) rights reserved.
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2015 Heart Rhythm Society. All
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.
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 http://dx.doi.org/10.1016/j.hrthm.2015.05.034
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Figure 1 Variance in freezing rate affects intracellular ice formation. At temperatures of 11C, little to no intracellular ice forms (A and C). Rapid freezing to 401C will result in more intracellular ice (D). Slow freezing to 401C yields less intracellular ice. If temperatures drop low enough, intracellular ice will form (B). Also note from panel A to B that cells shrink because of intracellular dehydration.19
constant pressure from a small vessel (such as tubing or catheter stem) into an expansion chamber.7 In the expansion chamber the liquefied gas converts to gas, resulting in absorption of heat to produce tissue cooling and freezing. Nitrogen, argon, and nitrous oxide cool upon expansion. Liquid nitrogen and argon respectively have boiling temperatures of 1961C and 185.91C at standard atmospheric pressure. These gases expand rapidly at room temperature, resulting in high pressure in the expansion chamber. Specialized vacuum containers are necessary for their storage and prevention of rupture. The size requirements of these instruments make them too large to be used transvenously, but surgical open-chest ablation procedures have been conducted using liquid nitrogen and argon probes.8,9 Nitrous oxide can be contained in a liquid state, but upon leaving its pressurized container it exists in a mixed liquefied gas state that can be used in percutaneous tools. Nitrous oxide has a boiling temperature of 88.471C, providing adequate cooling power and safety margins to be used in transvascular cardiac tissue ablation.
Mechanism of damage due to freezing Different cell types exhibit unique resistivity to freezing. The majority of cells appear to tolerate freezing temperatures between 01C and 151C for short periods.10,11 Because of the solute concentration levels present in cells, freezing does not typically occur until cells reach temperatures r51C.12 When temperatures reach 201C, the majority of cells die.11 The duration of freeze time necessary for cellular death is proportional to freezing temperature, with lower temperatures requiring shorter duration of freezing. Temperatures reaching r501C are always lethal, regardless of duration.11 The cause of variance in freezing rate between different cells is unclear, but research by Mazur13 suggests
Heart Rhythm, Vol 0, No 0, Month 2015 that water permeability of cellular membranes controls freezing rate. Regardless of cell type, cells react similarly to variable rates of freezing. At slow and fast rates, cell survivability is low, but at intermediate rates, survivability increases.11 This indicates that clinically the process of freezing should be either rapid or slow (freezing rate o1.67 or 46.671C/min) for the best outcomes. The process of freezing has been studied extensively since its discovery as a therapeutic medium in 1850 by Arnott,12 who used cryotherapy in the form of chilled saline to treat tumors. The use of cryoablation for treating arrhythmias was first tested in the 1970s.13 The freezing of cells and tissues is a complex process in which damage occurs both during the freezing process and afterward. There are 3 primary factors that contribute to damage from freezing done in vivo: direct cellular damage, vascular failure, and immunological effect.
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 51C to 151C.12 Nucleation begins in the extracellular space from the onset of cooling.16 Extracellular and intracellular ice formation results in dehydration as water crystallizes. Slow ice formation (r1.671C/min) results in extracellular ice crystals that expel salt, thereby increasing ion concentration in the extracellular space. This osmotic gradient shifts intracellular fluid to the extracellular space, dehydrating the cell and increasing the intracellular concentration of solutes to lethal levels.13 During slow freezes, the prolonged duration of osmotic dumping into extracellular space increases the duration of exposure to high concentrations of solutes17 (Figures 1A and B). Solute effects cause destruction by chemically denaturing or deactivating enzymes, proteins, and intracellular organelles.10,17 It has been shown that the exposure to the same concentration of electrolytes seen during freeze cycles is lethal to unfrozen red blood cells.16 Slow freezing depends on prolonged duration of exposure to high solute concentrations, but the lethality of fast freezing (Z6.671C/min) results from a shorter period of mechanical disruption caused by ice crystals. Analysis of cells after short periods of freezing (r60 seconds) reveals little mechanical damage to the ultrastructure of cells during initial ice formation.18 When freezing at very low temperatures is prolonged, ice crystals fracture and re-form into larger crystals. This process results in shearing forces and the formation of larger ice crystals that distend and disrupt cellular organelle, membranes, and small blood vessels.10,17 The formation of intracellular ice will in most cases result in cellular death.12
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Figure 2 Graphic image depicting different zones of freezing. The coldest temperature centers around the probe and warmer temperatures are in the zone of the ice ball, but the surrounding tissue is barely affected. As the distance from the probe increases, temperature and cell survivability rapidly increases. The bottom graph depicts the primary injury mechanism at a given temperature. Vascular injury has a large overlap with intracellular damage. Adjuvant approaches are immune response mechanisms that further damage.21
Intracellular and extracellular ice forms during both freezing processes, but vary in proportion. Rapid freezing results in proportionally more intracellular ice, whereas slow freezing results in more extracellular ice17 (Figure 1). A high proportion of intracellular ice yields destruction due to shearing, whereas a high proportion of extracellular ice yields destruction due to solute effects. Intracellular ice will form during slow freezes if temperature drops below 401C or freezing duration is sufficiently long (Figures 2B and D). Work by Gage et al11 found that freezing rates dramatically decrease with a rate difference of 101C/min seen in areas only a few millimeters from the cryoprobe. Tissue temperatures can be 5ºC warmer only 1 mm from the cryoprobe and become progressively and rapidly warmer as distance from the cryoprobe increases. Depending on the distance from the probe and temperature, different types of damage can occur in adjacent areas during cryoapplication (Figure 2). It is recommended to have a maximal cooling between 201C and 501C tissue temperature to account for variances.10 If this temperature range is not practical to reach, then it is important to freeze tissues to r201C and use long and repeated cycles. Direct cell injury is pivotal to the coagulative necrosis at the site of ice formation.18 The temperature and duration of freezing at these elevated temperatures may be insufficient to result in permanent injury, leaving cells in a sublethal state.17 A sublethal state is one in which cells are damaged but can potentially recover, depending on the immunological response and nutrient availability. While slow cooling rates can be as lethal as fast cooling rates, multiple factors such as blood perfusion, cryoprobe
contact, and cell resistivity can create a high degree of variability in ablation efficacy from one site to the next. Prolonged freeze duration to ensure proper ablation can make procedures unnecessarily long for both the patient and the operator. It is preferable to use especially fast rates, as this is more likely to result in lethality and in a shorter time span.
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 adjacent vessel cells to swell and rupture.11 This damage is the primary reason for vascular failure at the cryoprobe site and for peripheral microcirculation. Sublethal and unaffected cells respond to vascular failures at cryoprobe sites by sending vasoactive factors to promote reactive hyperemia of the area. These areas are exposed to the formation of free radicals that damage the lipids of the cellular membrane, causing structural failure. Blood vessels distend and weaken, and small/medium blood vessels are subject to thrombus formation.17 As smaller blood vessels become damaged, microcirculatory failure spreads and consolidates the direct cellular damage.
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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. Neutrophils at the ablation site latch onto adjacent blood vessel endothelium. Activation of neutrophils results in the by-product release of free radicals that damage the endothelium, contributing to thrombus formation in small blood vessels.17 As the endothelium degrades, the gap junctions between endothelial cells also degenerate and fluid, once held back, is released, leading to edema and ischemia.11 These mechanisms increased peripheral microvascular failure. Peripheral cells that were once sublethal or unaffected now become further stressed with killer T cells targeting and promoting apoptosis.20 It is important to recognize that although these injury mechanisms were placed in distinct sections, the reality is that these mechanisms occur simultaneously and are interrelated. Direct cellular damage causes the initial disruption of vasculature. The immune system responds to the injury and vascular stasis, but in doing so incidentally increased vascular failure and assists the death of partially damaged cells in the periphery. Proper lesion formation is related to acute damage from ablation and delayed effects during the inflammation and healing process.
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 ablation, hold time, and repeated procedure at a particular temperature are additional factors determining the extent of damage. Greater hold times at stable temperatures allow for equilibration, recrystallization, and more time for dehydration and solute effects to occur. There is much debate on sufficient duration for freeze, but it seems to depend on absolute temperature and freezing rate. Generally, as freezing temperatures approach 501C, shorter duration is necessary. However, once a temperature below 201C is reached, it should be maintained for at least 3 minutes.10,11,17,22,23 Support for this duration comes from data that suggest that the maximal lesion area is reached after 3 minutes during a single cryoballoon ablation procedure.22 This time can be reduced if the rate of freezing exceeds 6.671C/min or if the temperature in the tissue drops to r501C. Extension beyond this area requires repeated
Heart Rhythm, Vol 0, No 0, Month 2015 cycles. However, the freeze zone only needs to be restricted to thin tissues in contact with the cryoprobe, such as pulmonary vein (PV) antrum tissues. The duration of the cryoapplication should be titrated to transmural ice formation to prevent damage to extracardiac tissues such as esophageal, lung, and phrenic nerve.
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 thaw and return to ambient body temperature.
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 extending lesion boundaries. It should be noted that a recent clinical study has shown that successful PV isolation using a 28-mm cryoballoon can be accomplished by a single ablation procedure of 3 minutes.23 Repeat cycles are advantageous in ensuring successful ablation, but can increase the risk of extracardiac damage. It is also recommended to allow for a rest period between subsequent freezes. Rest periods between ablation procedures are poorly studied, but the limited data suggest improved outcomes.10 Ablated tissues allowed to rest are temporarily in a state of hemostasis. During this period, a greater breakdown of microcirculatory systems occurs and additional fluid builds up (hemorrhaging, lysed cells, and static blood). At this time, there is no defined rest period between ablation procedures, so length is arbitrary. One suggestion is to have a rest period of 2 minutes after tissue returns to ambient levels.
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. The heart in particular has high velocities of blood flow and highly vascularized tissues. As
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a consequence, it is difficult to extrapolate the freeze/thaw rates and absolute cold temperature of a cryoablation mechanism from data collected on other tissues and organs. To reliably overcome the variable effects of circulation, it is important to freeze at exceptionally low temperatures and repeat freezing cycles. Animal studies have shown that inducing cardioplegia to reduce perfusion effects and lower myocardial temperature result in larger lesions.8,24 However, this technique is unnecessarily invasive, potentially dangerous, and impractical, particularly when multiple ablation procedures are required. A minor factor affecting the lesion size is nitrous oxide tank pressure. One study showed that the maximal lesion size is reached when the tank pressure is Z700 psi. Tank pressure is dictated by the liquid-vapor equilibrium, which has a standard pressure of Z700 psi when liquid is present in the tank.25
blood vessels and shows minimal disruption of continuity to the adjacent myocardium.1,30 The majority of these findings were obtained in animal models, specifically canine and porcine, but were confirmed from human autopsies.31 Gross pathology and histology examples of wound healing and ablation procedures are shown in Figures 3A–F, and the time line of cryolesion injury and healing is shown in Figure 4.
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 01C and 281C (thermocouple reading from the catheter tip), it is reversibly suppressed and electrically silent without inducing a permanent injury.26 This suppression of sites can be used to determine the likelihood of successful cryotherapy, and tissue cryomapping can also help elucidate the mechanism for the arrhythmia. Cryomapping using the focal cryocatheters can be used to target tissues in close proximity to the His bundle, reducing the chance of creating permanent heart block.27 The same procedure was examined for ablation near the phrenic nerve and yielded favorable outcomes.28 However, it has been shown that the boundaries of cryoablation can extend beyond cryomapping and additional precautions should be taken during ablation procedures to prevent heart block.29
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 periphery of small blood vessels. The lesion site fills with differentiated fibroblasts, creating a moderate degree of fibrosis.30. After 12 weeks, the lesion is fibrotic and has no signs of hemorrhage, inflammation, or necrosis (Figure 3C). The lesion has a mixture of small and large
Effect on extracardiac structures Intracardiac ablation procedures can result in the extension of damage to extracardiac structures. Evidence of extracardiac damage is well documented in both preclinical and clinical trials, and this damage can include esophageal fistula, PV stenosis, phrenic nerve palsy, and potential lung hemolysis. Extracardiac damage can lead to potentially lifethreatening complications during and after the procedure. Extracardiac injuries can occur while using both the firstand, to a greater extent, second-generation cryoballoons, primarily involving the phrenic nerve, esophagus, and lung hemolysis. The focal cryoablation catheters have few reported complications in both adults and pediatric patients, with the exception of a moderate rate of reoccurrence (8.1%– 9.4%) when ablating AVNRT.32,33 Transient atrioventricular block (o10 seconds) has been reported, but is most likely caused by reversible suppression.32–34
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.35–39 Mild damage is characterized by superficial damage resulting from the mild degeneration of the muscular layer, myocyte straining, and mild edema. Severe damage features complete necrosis of myocytes, subsequent breakdown of the muscular layer, and mild to moderate edema.39 The healing process begins 1–4 days after ablation with re-epithelialization followed by fibroblast infiltration and mild to moderate fibrosis.37 During this period, any esophageal ulceration is at its most vulnerable, and physical (hard food) or chemical (gastric acid) stress may exacerbate the injury, leading to rupture. After 28 days, the wound appears histologically normal.36 Animal studies show that the esophagus is highly tolerant to damage from freezing. Freeze damage begins to occur at a temperature range of 01C to 101C,38 but the esophagus has been frozen to 1001C in felines, with complete recovery.36,40 Clinical research has shown that compared with RF ablation, cryoablation carries a lower risk of fistula formation and is less severe if it occurs.40 However, if the luminal esophageal temperature decreased by only 3.1ºC from ambient temperature (second to ablation procedures in the inferior veins), fistula formation was possible.41 Although fistula formation is less common with cryoenergy, it remains
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Figure 3 A: Acute unstained tissues obtained a few hours after 3-minute cryoablation depicts intense hemorrhage at the ablation site. B: 3 weeks postablation and C: 5 months postablation: tetrazolium blue stained unablated tissues (blue) and no stain uptake of the ablated tissues (white/yellow). As can be seen, little hemorrhage is present and the myocardium was replaced by fibrous tissues. D: Succession of four 3-minute cryolesions of the RSPV. Tissue was recovered 4.5 months after ablation. Notice the defined lesion boundaries and total isolation of the RSPV whereas the RMPV was not ablated. E: Transmural lesion on the RSPV harvested after 4.5 months. Four lesions were placed in this location. Lesions have discrete boundaries, the RSPV lesion is transmural, and no tissue thickening is noted. F: Trichrome stain of pulmonary vein tissue taken 3 months after ablation. Microscope analysis. The blue sections are ablated tissue, while the red sections are not. Notice the discrete boundaries between ablated and unablated tissue. No calcium or cartilage tissues are present despite several cryoabalation procedures per site. LIPV ¼ XXXX; LSPV ¼ XXXX; RIPV ¼ XXXX; RMPV ¼ XXXX; RSPV ¼ XXXX.
as difficult to detect as with RF. As a precaution, care should be taken not to add additional stress during the critical healing period of the esophagus (10 days postablation).
Respiratory structures It is possible for ablation procedures 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 o551C. This temperature is sufficient to induce cellular death, specifically necrosis. The proportion of ice at the PV was large enough to engulf lung tissues, causing small vessels to rupture, which resulted in hemoptysis.42 Research into the responsiveness of the respiratory system to freezing yields results similar to the esophagus. Respiratory structures tolerate a degree of freezing. One study used repeated procedures to directly freeze sections of the trachea in canines. After 12 hours, the animals were stable and tissue
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Figure 4
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Time line of cryolesion injury from acute ablation damage to chronic effects and healing. Six distinct sections are recognized.
analysis revealed necrosis at the ablation site that was well demarcated. The mucosal layer of the trachea began regenerating within days of the injury, and all animals recovered completely.44 After injury to lung tissues, re-epithelialization began within 72 hours and functionally healed within 2 weeks. Scarring was appreciable up to 3 weeks. Cartilage requires longer time to repair, with the healing process for cartilaginous structures beginning at 2 weeks.45 It is important to note that the regeneration of lobes does not occur. Although lung damage and hemoptysis have been reported in animals and humans, it is unlikely to lead to serious complications.44–46 While the complications may not be serious, extra caution should still be taken near these structures to minimize damage. Avoiding placement of the cryoballoon deep within the PV and limiting the freeze time if the temperatures are o501C will minimize the injury. Oversizing the PV ostial diameter by using an appropriately sized balloon will ensure that the balloon does not migrate into the PV.
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 lesion size. Small/medium blood vessels during this period have potential for thrombus formation. The degeneration and inflammation of the blood vessels occurs for 3–4 weeks, but regeneration begins at 2 weeks.47 The elastin fiber structure of the vessel is resistant to freezing, and in medium to large vessels it remains preserved despite cellular death.48 Proliferation of smooth muscle cells repairs vessels with minimal intimal narrowing and limited discontinuity with adjacent tissues.47 For small vessels the damage cannot be repaired and a new vascular system
develops in the wound site. Finally, ablation procedures in the heart that include damage to small blood vessels begin healing with capillary regrowth at the periphery, followed by infiltration of capillaries into the ablation site and restructuring of capillaries, forming a regular scattering of small and medium blood vessels.
Nerves Phrenic nerve palsy is a common complication of cryoablation. Propagation of ice formation from PVs that capture the nerve can temporarily or permanently suspend function. Nerves exhibit limited resistivity to freezing. An early study from 194549 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 study50 showed that the disruption of the myelin sheath and Schwann cell elements occurs, but nerves regenerate to normal functioning within 2 weeks of ablation. Damage to nerves occurs as a gradient based on temperature. Mild freezing from 01C to 5ºC results in minimal structural disruption and only temporary loss of function with immediate recovery upon thawing. From 5ºC to 415ºC, nerves will become damaged and may require weeks to heal. Freezing below 15ºC is likely to result in permanent damage.10 One study51 cites that nerves undergo Wallerian degeneration after ablation. The primary mode of destruction is large axonal loss. Furthermore, pacing of the phrenic nerve and diaphragmatic electromyographic monitoring during ablation is strongly advised. It has been shown that interruption of ablation when a 30% reduction in the diaphragmatic electromyogram was recorded resulted in a decrease of phrenic nerve palsy from 6% (average; range 3%–11%) to 1.5% with total recovery within 6 months.52
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
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Table 1
Heart Rhythm, Vol 0, No 0, Month 2015 Factors that affect cryoablation
Factor
Importance Primary impact
Probe size
High
Lowest temperature High Duration High Number of cycles
High
Cooling rate
High
Contact
High
Slow Thaw
Moderate
Rest period Moderate (postablation and thaw) Pressure in tank Minor Myocardial Mixed temperature/ perfusion
Notes
Lesion area and depth
Lesion area and depth increases with probe size. Size limitation inherent of the percutaneous method. Lesion area and depth Temperature r201C. Every 101C correlates to 0.38-mm increase in depth. Lesion area and depth Minimum 3 min at stable low temperature. 3–5 min has inconclusive results for broadening the lesion. Ensures tissue ablation. Z2 cycles. Subsequent cycles extend lesion boundaries and maximize necrosis Expanding the area at the probe site. and depth Improves tissue Data suggest no significant effect on lesion size, but low rates are impractical distraction clinically. High rates (Z51C/min) are suggested. Lesion formation Without contact, no lesion forms. When in contact, cryoadhesion stabilizes the cryoprobe against tissue. Efficacy of lesion Data are limited, but suggest that lesions defrosted using only body temperature improves the lethality of ablation. Lesion area depth and Research is limited, but available data suggest increased lesion area and efficacy improved efficacy. Lesion area Z700 psi for the maximal lesion size. Lesion area, depth, and Cardioplegia reduces myocardial temperature and perfusion. Improves lesion efficacy outcomes; however, the technique is impractical and potentially dangerous.
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 cryoballoons, without proper occlusion, blood flow streams along the balloon, severely restricting cooling and ice formation. Focal catheters can also experience diminished success in areas of high velocities of blood flow. Currently, operators have limited real-time information to predict the efficacy of ablation, increasing the likelihood of reoccurrence. To compensate for limited knowledge, ablation procedures should be of at least 2–3 minutes53,54 with a rest period lasting 2 minutes after ambient body temperature has been reached. A second ablation procedure at or near this area will result in faster and more efficient cooling, thereby improving efficacy. The naturally fast freezing process of nitrous oxide yields a high proportion of intracellular ice that requires a short period to create lethal shearing forces. The relative importance of these factors and others are summarized in Table 1. While these recommendations attempt to ensure ablation success, the possibility of extracardiac damage exists, though many tissues are resistant to permanent damage by freezing. Areas of concern are the esophagus, lungs, and the phrenic nerve. Avoiding placement of the balloon deep in the PVs will mitigate phrenic and excessive lung damage and create ostial PV isolation. Pacing and monitoring of the phrenic nerve is currently the most reliable safety precaution against palsy. Because damage to the esophagus can occur with little provocation, it is advised to instruct patients to eat soft foods, and for those patients prone to acid reflux, management using proton pump inhibitors postablation is advised.55 Although there is little to no data implicating stomach acid
or coarse food in fistula rupture, there are clinicians who would advise this regimen as risk prevention. Ultimately, restriction of the freeze zone to the atrial tissues by maintaining duration under 3 minutes is advisable. When ablating near the His bundle, it is recommended to use a focal cryocatheter and cryomap before ablation. Limitations of the monitoring capability of the cryoballoon system make titration of RF duration to lesion maturation difficult, which can result in a higher probability of reoccurrence or extracardiac damage. The current system provides temperature monitoring only in the balloon, which correlates poorly with the ice formation of the tissues.56 Ideally, tissue temperature could be obtained by placing temperature sensors and recording electrodes on or close to the balloon surface, which should greatly improve the monitoring of tissue cooling rate and interface temperature. The recording electrodes would establish the postablation efficacy. Given the cost and complexity of placing multiple temperature and electrodes on the balloon, an alternative option, currently under investigation, is to place Z1 temperature and impedance sensors on the shaft distal to the anterior surface of the balloon, providing the rate and thickness of ice formation.56
Uncited references 14; 15
Acknowledgments We thank the Engineering Department of the R&D section of Medtronic and Blake Fleeman, XX, for their editorial contributions.
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884 References 885Q28 1. Khairy P, Chauvet M, Lehman J, et al. Lower incidence of thrombus formation Q29 with cryoenergy versus radiofrequency catheter ablation. Circulation 2003;107: 886 2045–2050. 887 2. Avitall B, Khan M, Krum D, et al. Physics and engineering of transcatheter 888 cardiac tissue ablation. J Am Coll Cardiol 1993;22:921–932. 3. Haines DE. The biophysics of radiofrequency catheter ablation in the heart: the 889 importance of temperature monitoring. Pacing Clin Electrophysiol 1993;16:586–591. 890 4. Cooper IS. Cryogenic surgery: a new method of destruction or extirpation of 891 benign or malignant tissues. N Engl J Med 1963;268:743–749. 5. Fuernkranz A, Bordignon S, Schmidt B, et al. Improved procedural efficacy of 892 pulmonary vein isolation using the novel second‐generation cryoballoon. 893 J Cardiovasc Electrophysiol 2013;24:492–497. 894 6. Metzner A, Reissmann B, Rausch P, et al. One-year clinical outcome after pulmonary vein isolation using the second-generation 28-mm cryoballoon. Circ 895 Arrhythm Electrophysiol 2014;7:288–292. 896 7. Perry RH, Green DW, Maloney JO, eds. Perry’s Chemical Engineers’ Handbook. 897 New York: McGraw-Hill; 1984. 8. Ghalili K, Roth JA, Kwan SK, et al. Comparison of left ventricular cryolesions 898 created by liquid nitrogen and nitrous oxide. J Am Coll Cardiol 1992;20: 899 1425–1429. 900 9. Mack CA, Milla F, Ko W, et al. Surgical treatment of atrial fibrillation using argon-based cryoablation during concomitant cardiac procedures. Circulation 901 2005;112:I1–I6. 902 10. Baust JG, Gage AA. The molecular basis of cryosurgery. BJU Int 2005;95: 903 1187–1191. 904 11. Gage AA, Baust JM, Baust JG. Experimental cryosurgery investigations in vivo. Cryobiology 2009;59:229–243. 905 12. Gao D, Critser JK. Mechanisms of cryoinjury in living cells. ILAR J 2000;41: 906 187–196. 907 13. Mazur P. Kinetics of water loss from cells at subzero temperatures and the likelihood of intraocular freezing. J Gen Physiol 1963;47:347–369. 908 14. Arnott J. Practical illustrations of the remedial efficacy of a very low or 909 anaesthetic temperature. I. In cancer. Lancet 1850;2:257–259. 910 15. Harrison L, Gallagher JJ, Kasell J, Anderson RH, Mikat E, Hackel DB, Wallace AG. Cryosurgical ablation of the A-V node-His bundle: a new method for 911 producing A-V block. Circulation 1977;55:463–470. 912 16. Fowler A, Toner M. Cryo‐injury and biopreservation. Ann N Y Acad Sci 2006;1066:119–135. 913 17. Hoffmann NE, Bischof JC. The cryobiology of cryosurgical injury. Urology 914 2002;60:40–49. 915 18. Lustgarten DL, Keane D, Ruskin J. Cryothermal ablation: mechanism of tissue injury and current experience in the treatment of tachyarrhythmias. Progr 916 Cardiovasc Dis 1999;41:481–498. 917 19. Mehmet T, Cravalho EG, Karel M. Thermodynamics and kinetics of intracellular 918 ice formation during freezing of biological cells. J Appl Phys 1990;67: 1582–1593. 919 20. Sabel S. Cryo-immunology: a review of the literature and proposed mechanisms 920 for stimulatory versus suppressive immune responses. Cryobiology 2009;58: 921 1–11. 922 21. Goel R, Anderson K, Slaton J, et al. Adjuvant approaches to enhance cryosurgery. J Biomech Eng 2009;131:074003. 923Q30 22. Green DR. Means to an End: Apoptosis and Other Cell Death Mechanisms. In: 924 Cold Spring Harbor Laboratory Press; 2011. XXXX. 925Q31 23. Ciconte G, de Asmundis C, Sieira J, et al. Single three-minutes freeze for secondgeneration cryoballoon ablation: one-year follow-up following pulmonary vein 926 isolation. Heart Rhythm 2014;XX:XX–XX. 927 24. Dubuc M, Roy D, Thibault B, et al. Transvenous catheter ice mapping and cryoablation of the atrioventricular node in dogs. Pacing Clin Electrophysiol 928 1999;22:1488–1498. 929 25. Markovitz LJ, Frame LH, Josephson ME, Hargrove WC. Cardiac cryolesions: 930 factors affecting their size and a means of monitoring their formation. Ann Thorac Surg 1988;46:531–535. 931 26. Skanes AC, Dubuc M, Klein GJ, et al. Cryothermal ablation of the slow pathway 932 for the elimination of atrioventricular nodal reentrant tachycardia. Circulation 933 2000;102:2856–2860. 934 27. Dib C, Kapa S, Powell BD. Successful use of “cryo-mapping” to avoid phrenic nerve damage during ostial superior vena caval ablation despite nerve proximity. 935 J Interv Card Electrophysiol 2008;22:23–30. 936 28. Wong T, Markides V, Peters NS, Davies DW. Clinical usefulness of cryomapping for ablation of tachycardias involving perinodal tissue. J Interv Card 937 Electrophysiol 2004;10:153–158. 938 29. Fischbach PS, Saarel EV, Dick M. Transient atrioventricular conduction block 939 with cryoablation following normal cryomapping. Heart Rhythm 2004;1: 554–557. 940
30. Fujino H, Thompson RP, Germroth PG, et al. Histologic study of chronic catheter cryoablation of atrioventricular conduction in swine. Am Heart J 1993;125: 1632–1637. 31. Wells P. Cryothermic ablation in comparison with radiofrequency ablation. Heartracing.com Web site. http://www.heartracing.com/physicians/cryothermic. ablation.asp. Accessed XXXX XX, XX. 32. Rivard L, Dubuc M, Guerra PG, et al. Cryoablation outcomes for AV nodal reentrant tachycardia comparing 4-mm versus 6-mm electrode-tip catheters. Heart Rhythm 2008;5:230–234. 33. Deisenhofer I, Zrenner B, Yin Y-H, et al. Cryoablation versus radiofrequency energy for the ablation of atrioventricular nodal reentrant tachycardia (the CYRANO Study): results from a large multicenter prospective randomized trial. Circulation 2010;122:2239–2245. 34. Avari JN, Jay KS, Rhee EK. Experience and results during transition from radiofrequency ablation to cryoablation for treatment of pediatric atrioventricular nodal reentrant tachycardia. Pacing Clin Electrophysiol 2008;31:454–460. 35. Ohkawa S, Hackel DB, Mikat EM, et al. Anatomic effects of cryoablation of the atrioventricular conduction system. Circulation 1982;65:1155–1162. 36. Rodgers BM, McDonald AP, Talbert JL, Donnelly WH. Morphologic and functional effects of esophageal cryotherapy. J Thorac Cardiovasc Surg 1979;77: 543–549. 37. Pasricha PJ, Hill S, Wadwa KS, et al. Endoscopic cryotherapy: experimental results and first clinical use. Gastrointest Endosc 1999;49:627–631. 38. Johnston CM, Schoenfeld LP, Mysore JV, Dubois A. Endoscopic spray cryotherapy: a new technique for mucosal ablation in the esophagus. Gastrointest Endosc 1999;50:86–92. 39. Aupperle H, Doll N, Walther T, Kornherr P, Ullmann C, Schoon HA, Mohr FW. Ablation of atrial fibrillation and esophageal injury: effects of energy source and ablation technique. J Thorac Cardiovasc Surg 2005;130:1549–1554. 40. Rodgers BM, Pappelis P. Profound endoesophageal cryotherapy. Cryobiology 1985;22:86–92. 41. Avitall B, Lafontaine D, Rozmus G, et al. The safety and efficacy of multiple consecutive cryo lesions in canine pulmonary veins-left atrial junction. Heart Rhythm 2004;1:203–209. 42. Kumar N, Timmermans C, Das M, Dassen W, Philippens S, Maessen J, Crijns HJ. Hemoptysis after cryoablation for atrial fibrillation: truth or just a myth? Chest 2014;146;XX–XX. 43. Neel HB III, Farrell KH, DeSanto LW, Payne WS, Sanderson DR. Cryosurgery of respiratory structures. I. Cryonecrosis of trachea and bronchus. Laryngoscope 1973;83:1062–1071. 44. Neel HB III, Farrell KH, Payne WS, DeSanto LW. Cryosurgery of respiratory structures II. Cryonecrosis of the lung. Laryngoscope 1974;84:417–426. 45. Izumi Y, Oyama T, Ikeda E, Kawamura M, Kobayashi K. The acute effects of transthoracic cryoablation on normal lung evaluated in a porcine model. Ann Thorac Surg 2005;79:318–322. 46. Cooper IS, Samra K, Wisniewska K. Effects of freezing on major arteries. Stroke 1971;2:471–482. 47. Ladd AP, Rescorla FJ, Baust JG, et al. Cryosurgical effects on growing vessels. Am Surg 1999;65:677–682. 48. Denny-Brown D, Adams RD, Brenner C, Doherty MM. The pathology of injury to nerve induced by cold. J Neuropathol Exp Neurol 1945;4:305–323. 49. Whittaker DK. Degeneration and regeneration of nerves following cryosurgery. Br J Exp Pathol 1974;55:595. 50. Kawasaki R, Gauri A, Elmouchi D, Duggal M, Bhan A. Atrioesophageal fistula complicating cryoballoon pulmonary vein isolation for paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2014;XX:XX–XX. 51. Andrade JG, Dubuc M, Ferreira J, et al. Histopathology of cryoballoon ablation‐ induced phrenic nerve injury. J Cardiovasc Electrophysiol 2014;25:187–194. 52. Mondésert B, Andrade JG, Khairy P, et al. Clinical experience with a novel electromyographic approach to preventing phrenic nerve injury during cryoballoon ablation in atrial fibrillation. Circ Arrhythm Electrophysiol 2014;XX:XX– XX. 53. Chierchia G-B, Di Giovanni G, Sieira-Moret J, et al. Initial experience of threeminute freeze cycles using the second-generation cryoballoon ablation: acute and short-term procedural outcomes. J Interv Card Electrophysiol 2014;39:145–151. 54. Andrade JG, Dubuc M, Guerra PG, et al. Pulmonary vein isolation using a second‐generation cryoballoon catheter: a randomized comparison of ablation duration and method of deflation. J Cardiovasc Electrophysiol 2013;24:692–698. 55. Lim HW, Cogert GA, Cameron CS, et al. Atrioesophageal fistula during cryoballoon ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014;25: 208–213. 56. Avitall B, Horbal P, Vance D, Laske T. A new cryo balloon efficacy and safety monitoring: distal balloon impedance and temperature recording. Paper presented at Heart Rhythm Society 35th Annual Scientific Sessions; XXXX XX, 2014; San Francisco, CA. Abstract XX.
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CONTEMPORARY REVIEW
Cryotherapy of cardiac arrhythmia: From basic science to the bedside Boaz Avitall, MD, PhD, FHRS, Arthur Kalinski, BS From the University of Illinois at Chicago, Chicago, Illinois. This review focuses on the basic science of cellular destruction by tissue freezing and application to treat cardiac arrhythmia with the use of transvenous cryocatheter technology. Ideally, foci for arrhythmias are selectively ablated, arrhythmogenic tissues are destroyed, and reentry circuits are bisected in order to silence adverse electrical activity, with the goal of restoring normal sinus rhythm. The mechanism of ablation using cryotherapy results in distinct lesion qualities advantageous to radiofrequency (Khairy P, Chauvet M, Lehman J, et al. Lower incidence of thrombus formation with cryoenergy versus radiofrequency catheter ablation. Circulation 2003;107:2045–2050). This review is devoted to the mechanism of cryoablation, postablation histopathological changes, and
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 8mm 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 JouleThomson effect (J-T effect). In the adult patient, focal
Address reprint requests and correspondence: Dr Boaz Avitall, University of Illinois at Chicago, 840 S Wood St, Suite 922, Chicago, IL 60612. E-mail address: [email protected]. Dr Avitall is a paid consultant to Medtronic, which is currently the primary producer of cryotherapy products for electrophysiology.
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
how this information should be used by the clinicians to improve safety and maximize ablation success. KEYWORDS Cryoablation; Pulmonary vein isolation; Arrhythmia; Cryoballoon ABBREVIATIONS AVNRT ¼ atrioventricular nodal reentry tachycardia; J-T effect ¼ Joule-Thomson effect; PV ¼ pulmonary vein; RF ¼ radiofrequency (Heart Rhythm 2015;0:-3–9) rights reserved.
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2015 Heart Rhythm Society. All
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.
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 http://dx.doi.org/10.1016/j.hrthm.2015.05.034
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Figure 1 Variance in freezing rate affects intracellular ice formation. At temperatures of 11C, little to no intracellular ice forms (A and C). Rapid freezing to 401C will result in more intracellular ice (D). Slow freezing to 401C yields less intracellular ice. If temperatures drop low enough, intracellular ice will form (B). Also note from panel A to B that cells shrink because of intracellular dehydration.19
constant pressure from a small vessel (such as tubing or catheter stem) into an expansion chamber.7 In the expansion chamber the liquefied gas converts to gas, resulting in absorption of heat to produce tissue cooling and freezing. Nitrogen, argon, and nitrous oxide cool upon expansion. Liquid nitrogen and argon respectively have boiling temperatures of 1961C and 185.91C at standard atmospheric pressure. These gases expand rapidly at room temperature, resulting in high pressure in the expansion chamber. Specialized vacuum containers are necessary for their storage and prevention of rupture. The size requirements of these instruments make them too large to be used transvenously, but surgical open-chest ablation procedures have been conducted using liquid nitrogen and argon probes.8,9 Nitrous oxide can be contained in a liquid state, but upon leaving its pressurized container it exists in a mixed liquefied gas state that can be used in percutaneous tools. Nitrous oxide has a boiling temperature of 88.471C, providing adequate cooling power and safety margins to be used in transvascular cardiac tissue ablation.
Mechanism of damage due to freezing Different cell types exhibit unique resistivity to freezing. The majority of cells appear to tolerate freezing temperatures between 01C and 151C for short periods.10,11 Because of the solute concentration levels present in cells, freezing does not typically occur until cells reach temperatures r51C.12 When temperatures reach 201C, the majority of cells die.11 The duration of freeze time necessary for cellular death is proportional to freezing temperature, with lower temperatures requiring shorter duration of freezing. Temperatures reaching r501C are always lethal, regardless of duration.11 The cause of variance in freezing rate between different cells is unclear, but research by Mazur13 suggests
Heart Rhythm, Vol 0, No 0, Month 2015 that water permeability of cellular membranes controls freezing rate. Regardless of cell type, cells react similarly to variable rates of freezing. At slow and fast rates, cell survivability is low, but at intermediate rates, survivability increases.11 This indicates that clinically the process of freezing should be either rapid or slow (freezing rate o1.67 or 46.671C/min) for the best outcomes. The process of freezing has been studied extensively since its discovery as a therapeutic medium in 1850 by Arnott,12 who used cryotherapy in the form of chilled saline to treat tumors. The use of cryoablation for treating arrhythmias was first tested in the 1970s.13 The freezing of cells and tissues is a complex process in which damage occurs both during the freezing process and afterward. There are 3 primary factors that contribute to damage from freezing done in vivo: direct cellular damage, vascular failure, and immunological effect.
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 51C to 151C.12 Nucleation begins in the extracellular space from the onset of cooling.16 Extracellular and intracellular ice formation results in dehydration as water crystallizes. Slow ice formation (r1.671C/min) results in extracellular ice crystals that expel salt, thereby increasing ion concentration in the extracellular space. This osmotic gradient shifts intracellular fluid to the extracellular space, dehydrating the cell and increasing the intracellular concentration of solutes to lethal levels.13 During slow freezes, the prolonged duration of osmotic dumping into extracellular space increases the duration of exposure to high concentrations of solutes17 (Figures 1A and B). Solute effects cause destruction by chemically denaturing or deactivating enzymes, proteins, and intracellular organelles.10,17 It has been shown that the exposure to the same concentration of electrolytes seen during freeze cycles is lethal to unfrozen red blood cells.16 Slow freezing depends on prolonged duration of exposure to high solute concentrations, but the lethality of fast freezing (Z6.671C/min) results from a shorter period of mechanical disruption caused by ice crystals. Analysis of cells after short periods of freezing (r60 seconds) reveals little mechanical damage to the ultrastructure of cells during initial ice formation.18 When freezing at very low temperatures is prolonged, ice crystals fracture and re-form into larger crystals. This process results in shearing forces and the formation of larger ice crystals that distend and disrupt cellular organelle, membranes, and small blood vessels.10,17 The formation of intracellular ice will in most cases result in cellular death.12
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Figure 2 Graphic image depicting different zones of freezing. The coldest temperature centers around the probe and warmer temperatures are in the zone of the ice ball, but the surrounding tissue is barely affected. As the distance from the probe increases, temperature and cell survivability rapidly increases. The bottom graph depicts the primary injury mechanism at a given temperature. Vascular injury has a large overlap with intracellular damage. Adjuvant approaches are immune response mechanisms that further damage.21
Intracellular and extracellular ice forms during both freezing processes, but vary in proportion. Rapid freezing results in proportionally more intracellular ice, whereas slow freezing results in more extracellular ice17 (Figure 1). A high proportion of intracellular ice yields destruction due to shearing, whereas a high proportion of extracellular ice yields destruction due to solute effects. Intracellular ice will form during slow freezes if temperature drops below 401C or freezing duration is sufficiently long (Figures 2B and D). Work by Gage et al11 found that freezing rates dramatically decrease with a rate difference of 101C/min seen in areas only a few millimeters from the cryoprobe. Tissue temperatures can be 5ºC warmer only 1 mm from the cryoprobe and become progressively and rapidly warmer as distance from the cryoprobe increases. Depending on the distance from the probe and temperature, different types of damage can occur in adjacent areas during cryoapplication (Figure 2). It is recommended to have a maximal cooling between 201C and 501C tissue temperature to account for variances.10 If this temperature range is not practical to reach, then it is important to freeze tissues to r201C and use long and repeated cycles. Direct cell injury is pivotal to the coagulative necrosis at the site of ice formation.18 The temperature and duration of freezing at these elevated temperatures may be insufficient to result in permanent injury, leaving cells in a sublethal state.17 A sublethal state is one in which cells are damaged but can potentially recover, depending on the immunological response and nutrient availability. While slow cooling rates can be as lethal as fast cooling rates, multiple factors such as blood perfusion, cryoprobe
contact, and cell resistivity can create a high degree of variability in ablation efficacy from one site to the next. Prolonged freeze duration to ensure proper ablation can make procedures unnecessarily long for both the patient and the operator. It is preferable to use especially fast rates, as this is more likely to result in lethality and in a shorter time span.
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 adjacent vessel cells to swell and rupture.11 This damage is the primary reason for vascular failure at the cryoprobe site and for peripheral microcirculation. Sublethal and unaffected cells respond to vascular failures at cryoprobe sites by sending vasoactive factors to promote reactive hyperemia of the area. These areas are exposed to the formation of free radicals that damage the lipids of the cellular membrane, causing structural failure. Blood vessels distend and weaken, and small/medium blood vessels are subject to thrombus formation.17 As smaller blood vessels become damaged, microcirculatory failure spreads and consolidates the direct cellular damage.
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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. Neutrophils at the ablation site latch onto adjacent blood vessel endothelium. Activation of neutrophils results in the by-product release of free radicals that damage the endothelium, contributing to thrombus formation in small blood vessels.17 As the endothelium degrades, the gap junctions between endothelial cells also degenerate and fluid, once held back, is released, leading to edema and ischemia.11 These mechanisms increased peripheral microvascular failure. Peripheral cells that were once sublethal or unaffected now become further stressed with killer T cells targeting and promoting apoptosis.20 It is important to recognize that although these injury mechanisms were placed in distinct sections, the reality is that these mechanisms occur simultaneously and are interrelated. Direct cellular damage causes the initial disruption of vasculature. The immune system responds to the injury and vascular stasis, but in doing so incidentally increased vascular failure and assists the death of partially damaged cells in the periphery. Proper lesion formation is related to acute damage from ablation and delayed effects during the inflammation and healing process.
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 ablation, hold time, and repeated procedure at a particular temperature are additional factors determining the extent of damage. Greater hold times at stable temperatures allow for equilibration, recrystallization, and more time for dehydration and solute effects to occur. There is much debate on sufficient duration for freeze, but it seems to depend on absolute temperature and freezing rate. Generally, as freezing temperatures approach 501C, shorter duration is necessary. However, once a temperature below 201C is reached, it should be maintained for at least 3 minutes.10,11,17,22,23 Support for this duration comes from data that suggest that the maximal lesion area is reached after 3 minutes during a single cryoballoon ablation procedure.22 This time can be reduced if the rate of freezing exceeds 6.671C/min or if the temperature in the tissue drops to r501C. Extension beyond this area requires repeated
Heart Rhythm, Vol 0, No 0, Month 2015 cycles. However, the freeze zone only needs to be restricted to thin tissues in contact with the cryoprobe, such as pulmonary vein (PV) antrum tissues. The duration of the cryoapplication should be titrated to transmural ice formation to prevent damage to extracardiac tissues such as esophageal, lung, and phrenic nerve.
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 thaw and return to ambient body temperature.
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 extending lesion boundaries. It should be noted that a recent clinical study has shown that successful PV isolation using a 28-mm cryoballoon can be accomplished by a single ablation procedure of 3 minutes.23 Repeat cycles are advantageous in ensuring successful ablation, but can increase the risk of extracardiac damage. It is also recommended to allow for a rest period between subsequent freezes. Rest periods between ablation procedures are poorly studied, but the limited data suggest improved outcomes.10 Ablated tissues allowed to rest are temporarily in a state of hemostasis. During this period, a greater breakdown of microcirculatory systems occurs and additional fluid builds up (hemorrhaging, lysed cells, and static blood). At this time, there is no defined rest period between ablation procedures, so length is arbitrary. One suggestion is to have a rest period of 2 minutes after tissue returns to ambient levels.
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. The heart in particular has high velocities of blood flow and highly vascularized tissues. As
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a consequence, it is difficult to extrapolate the freeze/thaw rates and absolute cold temperature of a cryoablation mechanism from data collected on other tissues and organs. To reliably overcome the variable effects of circulation, it is important to freeze at exceptionally low temperatures and repeat freezing cycles. Animal studies have shown that inducing cardioplegia to reduce perfusion effects and lower myocardial temperature result in larger lesions.8,24 However, this technique is unnecessarily invasive, potentially dangerous, and impractical, particularly when multiple ablation procedures are required. A minor factor affecting the lesion size is nitrous oxide tank pressure. One study showed that the maximal lesion size is reached when the tank pressure is Z700 psi. Tank pressure is dictated by the liquid-vapor equilibrium, which has a standard pressure of Z700 psi when liquid is present in the tank.25
blood vessels and shows minimal disruption of continuity to the adjacent myocardium.1,30 The majority of these findings were obtained in animal models, specifically canine and porcine, but were confirmed from human autopsies.31 Gross pathology and histology examples of wound healing and ablation procedures are shown in Figures 3A–F, and the time line of cryolesion injury and healing is shown in Figure 4.
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 01C and 281C (thermocouple reading from the catheter tip), it is reversibly suppressed and electrically silent without inducing a permanent injury.26 This suppression of sites can be used to determine the likelihood of successful cryotherapy, and tissue cryomapping can also help elucidate the mechanism for the arrhythmia. Cryomapping using the focal cryocatheters can be used to target tissues in close proximity to the His bundle, reducing the chance of creating permanent heart block.27 The same procedure was examined for ablation near the phrenic nerve and yielded favorable outcomes.28 However, it has been shown that the boundaries of cryoablation can extend beyond cryomapping and additional precautions should be taken during ablation procedures to prevent heart block.29
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 periphery of small blood vessels. The lesion site fills with differentiated fibroblasts, creating a moderate degree of fibrosis.30. After 12 weeks, the lesion is fibrotic and has no signs of hemorrhage, inflammation, or necrosis (Figure 3C). The lesion has a mixture of small and large
Effect on extracardiac structures Intracardiac ablation procedures can result in the extension of damage to extracardiac structures. Evidence of extracardiac damage is well documented in both preclinical and clinical trials, and this damage can include esophageal fistula, PV stenosis, phrenic nerve palsy, and potential lung hemolysis. Extracardiac damage can lead to potentially lifethreatening complications during and after the procedure. Extracardiac injuries can occur while using both the firstand, to a greater extent, second-generation cryoballoons, primarily involving the phrenic nerve, esophagus, and lung hemolysis. The focal cryoablation catheters have few reported complications in both adults and pediatric patients, with the exception of a moderate rate of reoccurrence (8.1%– 9.4%) when ablating AVNRT.32,33 Transient atrioventricular block (o10 seconds) has been reported, but is most likely caused by reversible suppression.32–34
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.35–39 Mild damage is characterized by superficial damage resulting from the mild degeneration of the muscular layer, myocyte straining, and mild edema. Severe damage features complete necrosis of myocytes, subsequent breakdown of the muscular layer, and mild to moderate edema.39 The healing process begins 1–4 days after ablation with re-epithelialization followed by fibroblast infiltration and mild to moderate fibrosis.37 During this period, any esophageal ulceration is at its most vulnerable, and physical (hard food) or chemical (gastric acid) stress may exacerbate the injury, leading to rupture. After 28 days, the wound appears histologically normal.36 Animal studies show that the esophagus is highly tolerant to damage from freezing. Freeze damage begins to occur at a temperature range of 01C to 101C,38 but the esophagus has been frozen to 1001C in felines, with complete recovery.36,40 Clinical research has shown that compared with RF ablation, cryoablation carries a lower risk of fistula formation and is less severe if it occurs.40 However, if the luminal esophageal temperature decreased by only 3.1ºC from ambient temperature (second to ablation procedures in the inferior veins), fistula formation was possible.41 Although fistula formation is less common with cryoenergy, it remains
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Figure 3 A: Acute unstained tissues obtained a few hours after 3-minute cryoablation depicts intense hemorrhage at the ablation site. B: 3 weeks postablation and C: 5 months postablation: tetrazolium blue stained unablated tissues (blue) and no stain uptake of the ablated tissues (white/yellow). As can be seen, little hemorrhage is present and the myocardium was replaced by fibrous tissues. D: Succession of four 3-minute cryolesions of the RSPV. Tissue was recovered 4.5 months after ablation. Notice the defined lesion boundaries and total isolation of the RSPV whereas the RMPV was not ablated. E: Transmural lesion on the RSPV harvested after 4.5 months. Four lesions were placed in this location. Lesions have discrete boundaries, the RSPV lesion is transmural, and no tissue thickening is noted. F: Trichrome stain of pulmonary vein tissue taken 3 months after ablation. Microscope analysis. The blue sections are ablated tissue, while the red sections are not. Notice the discrete boundaries between ablated and unablated tissue. No calcium or cartilage tissues are present despite several cryoabalation procedures per site. LIPV ¼ XXXX; LSPV ¼ XXXX; RIPV ¼ XXXX; RMPV ¼ XXXX; RSPV ¼ XXXX.
as difficult to detect as with RF. As a precaution, care should be taken not to add additional stress during the critical healing period of the esophagus (10 days postablation).
Respiratory structures It is possible for ablation procedures 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 o551C. This temperature is sufficient to induce cellular death, specifically necrosis. The proportion of ice at the PV was large enough to engulf lung tissues, causing small vessels to rupture, which resulted in hemoptysis.42 Research into the responsiveness of the respiratory system to freezing yields results similar to the esophagus. Respiratory structures tolerate a degree of freezing. One study used repeated procedures to directly freeze sections of the trachea in canines. After 12 hours, the animals were stable and tissue
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Figure 4
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Time line of cryolesion injury from acute ablation damage to chronic effects and healing. Six distinct sections are recognized.
analysis revealed necrosis at the ablation site that was well demarcated. The mucosal layer of the trachea began regenerating within days of the injury, and all animals recovered completely.44 After injury to lung tissues, re-epithelialization began within 72 hours and functionally healed within 2 weeks. Scarring was appreciable up to 3 weeks. Cartilage requires longer time to repair, with the healing process for cartilaginous structures beginning at 2 weeks.45 It is important to note that the regeneration of lobes does not occur. Although lung damage and hemoptysis have been reported in animals and humans, it is unlikely to lead to serious complications.44–46 While the complications may not be serious, extra caution should still be taken near these structures to minimize damage. Avoiding placement of the cryoballoon deep within the PV and limiting the freeze time if the temperatures are o501C will minimize the injury. Oversizing the PV ostial diameter by using an appropriately sized balloon will ensure that the balloon does not migrate into the PV.
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 lesion size. Small/medium blood vessels during this period have potential for thrombus formation. The degeneration and inflammation of the blood vessels occurs for 3–4 weeks, but regeneration begins at 2 weeks.47 The elastin fiber structure of the vessel is resistant to freezing, and in medium to large vessels it remains preserved despite cellular death.48 Proliferation of smooth muscle cells repairs vessels with minimal intimal narrowing and limited discontinuity with adjacent tissues.47 For small vessels the damage cannot be repaired and a new vascular system
develops in the wound site. Finally, ablation procedures in the heart that include damage to small blood vessels begin healing with capillary regrowth at the periphery, followed by infiltration of capillaries into the ablation site and restructuring of capillaries, forming a regular scattering of small and medium blood vessels.
Nerves Phrenic nerve palsy is a common complication of cryoablation. Propagation of ice formation from PVs that capture the nerve can temporarily or permanently suspend function. Nerves exhibit limited resistivity to freezing. An early study from 194549 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 study50 showed that the disruption of the myelin sheath and Schwann cell elements occurs, but nerves regenerate to normal functioning within 2 weeks of ablation. Damage to nerves occurs as a gradient based on temperature. Mild freezing from 01C to 5ºC results in minimal structural disruption and only temporary loss of function with immediate recovery upon thawing. From 5ºC to 415ºC, nerves will become damaged and may require weeks to heal. Freezing below 15ºC is likely to result in permanent damage.10 One study51 cites that nerves undergo Wallerian degeneration after ablation. The primary mode of destruction is large axonal loss. Furthermore, pacing of the phrenic nerve and diaphragmatic electromyographic monitoring during ablation is strongly advised. It has been shown that interruption of ablation when a 30% reduction in the diaphragmatic electromyogram was recorded resulted in a decrease of phrenic nerve palsy from 6% (average; range 3%–11%) to 1.5% with total recovery within 6 months.52
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
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Table 1
Heart Rhythm, Vol 0, No 0, Month 2015 Factors that affect cryoablation
Factor
Importance Primary impact
Probe size
High
Lowest temperature High Duration High Number of cycles
High
Cooling rate
High
Contact
High
Slow Thaw
Moderate
Rest period Moderate (postablation and thaw) Pressure in tank Minor Myocardial Mixed temperature/ perfusion
Notes
Lesion area and depth
Lesion area and depth increases with probe size. Size limitation inherent of the percutaneous method. Lesion area and depth Temperature r201C. Every 101C correlates to 0.38-mm increase in depth. Lesion area and depth Minimum 3 min at stable low temperature. 3–5 min has inconclusive results for broadening the lesion. Ensures tissue ablation. Z2 cycles. Subsequent cycles extend lesion boundaries and maximize necrosis Expanding the area at the probe site. and depth Improves tissue Data suggest no significant effect on lesion size, but low rates are impractical distraction clinically. High rates (Z51C/min) are suggested. Lesion formation Without contact, no lesion forms. When in contact, cryoadhesion stabilizes the cryoprobe against tissue. Efficacy of lesion Data are limited, but suggest that lesions defrosted using only body temperature improves the lethality of ablation. Lesion area depth and Research is limited, but available data suggest increased lesion area and efficacy improved efficacy. Lesion area Z700 psi for the maximal lesion size. Lesion area, depth, and Cardioplegia reduces myocardial temperature and perfusion. Improves lesion efficacy outcomes; however, the technique is impractical and potentially dangerous.
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 cryoballoons, without proper occlusion, blood flow streams along the balloon, severely restricting cooling and ice formation. Focal catheters can also experience diminished success in areas of high velocities of blood flow. Currently, operators have limited real-time information to predict the efficacy of ablation, increasing the likelihood of reoccurrence. To compensate for limited knowledge, ablation procedures should be of at least 2–3 minutes53,54 with a rest period lasting 2 minutes after ambient body temperature has been reached. A second ablation procedure at or near this area will result in faster and more efficient cooling, thereby improving efficacy. The naturally fast freezing process of nitrous oxide yields a high proportion of intracellular ice that requires a short period to create lethal shearing forces. The relative importance of these factors and others are summarized in Table 1. While these recommendations attempt to ensure ablation success, the possibility of extracardiac damage exists, though many tissues are resistant to permanent damage by freezing. Areas of concern are the esophagus, lungs, and the phrenic nerve. Avoiding placement of the balloon deep in the PVs will mitigate phrenic and excessive lung damage and create ostial PV isolation. Pacing and monitoring of the phrenic nerve is currently the most reliable safety precaution against palsy. Because damage to the esophagus can occur with little provocation, it is advised to instruct patients to eat soft foods, and for those patients prone to acid reflux, management using proton pump inhibitors postablation is advised.55 Although there is little to no data implicating stomach acid
or coarse food in fistula rupture, there are clinicians who would advise this regimen as risk prevention. Ultimately, restriction of the freeze zone to the atrial tissues by maintaining duration under 3 minutes is advisable. When ablating near the His bundle, it is recommended to use a focal cryocatheter and cryomap before ablation. Limitations of the monitoring capability of the cryoballoon system make titration of RF duration to lesion maturation difficult, which can result in a higher probability of reoccurrence or extracardiac damage. The current system provides temperature monitoring only in the balloon, which correlates poorly with the ice formation of the tissues.56 Ideally, tissue temperature could be obtained by placing temperature sensors and recording electrodes on or close to the balloon surface, which should greatly improve the monitoring of tissue cooling rate and interface temperature. The recording electrodes would establish the postablation efficacy. Given the cost and complexity of placing multiple temperature and electrodes on the balloon, an alternative option, currently under investigation, is to place Z1 temperature and impedance sensors on the shaft distal to the anterior surface of the balloon, providing the rate and thickness of ice formation.56
Uncited references 14; 15
Acknowledgments We thank the Engineering Department of the R&D section of Medtronic and Blake Fleeman, XX, for their editorial contributions.
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30. Fujino H, Thompson RP, Germroth PG, et al. Histologic study of chronic catheter cryoablation of atrioventricular conduction in swine. Am Heart J 1993;125: 1632–1637. 31. Wells P. Cryothermic ablation in comparison with radiofrequency ablation. Heartracing.com Web site. http://www.heartracing.com/physicians/cryothermic. ablation.asp. Accessed XXXX XX, XX. 32. Rivard L, Dubuc M, Guerra PG, et al. Cryoablation outcomes for AV nodal reentrant tachycardia comparing 4-mm versus 6-mm electrode-tip catheters. Heart Rhythm 2008;5:230–234. 33. Deisenhofer I, Zrenner B, Yin Y-H, et al. Cryoablation versus radiofrequency energy for the ablation of atrioventricular nodal reentrant tachycardia (the CYRANO Study): results from a large multicenter prospective randomized trial. Circulation 2010;122:2239–2245. 34. Avari JN, Jay KS, Rhee EK. Experience and results during transition from radiofrequency ablation to cryoablation for treatment of pediatric atrioventricular nodal reentrant tachycardia. Pacing Clin Electrophysiol 2008;31:454–460. 35. Ohkawa S, Hackel DB, Mikat EM, et al. Anatomic effects of cryoablation of the atrioventricular conduction system. Circulation 1982;65:1155–1162. 36. Rodgers BM, McDonald AP, Talbert JL, Donnelly WH. Morphologic and functional effects of esophageal cryotherapy. J Thorac Cardiovasc Surg 1979;77: 543–549. 37. Pasricha PJ, Hill S, Wadwa KS, et al. Endoscopic cryotherapy: experimental results and first clinical use. Gastrointest Endosc 1999;49:627–631. 38. Johnston CM, Schoenfeld LP, Mysore JV, Dubois A. Endoscopic spray cryotherapy: a new technique for mucosal ablation in the esophagus. Gastrointest Endosc 1999;50:86–92. 39. Aupperle H, Doll N, Walther T, Kornherr P, Ullmann C, Schoon HA, Mohr FW. Ablation of atrial fibrillation and esophageal injury: effects of energy source and ablation technique. J Thorac Cardiovasc Surg 2005;130:1549–1554. 40. Rodgers BM, Pappelis P. Profound endoesophageal cryotherapy. Cryobiology 1985;22:86–92. 41. Avitall B, Lafontaine D, Rozmus G, et al. The safety and efficacy of multiple consecutive cryo lesions in canine pulmonary veins-left atrial junction. Heart Rhythm 2004;1:203–209. 42. Kumar N, Timmermans C, Das M, Dassen W, Philippens S, Maessen J, Crijns HJ. Hemoptysis after cryoablation for atrial fibrillation: truth or just a myth? Chest 2014;146;XX–XX. 43. Neel HB III, Farrell KH, DeSanto LW, Payne WS, Sanderson DR. Cryosurgery of respiratory structures. I. Cryonecrosis of trachea and bronchus. Laryngoscope 1973;83:1062–1071. 44. Neel HB III, Farrell KH, Payne WS, DeSanto LW. Cryosurgery of respiratory structures II. Cryonecrosis of the lung. Laryngoscope 1974;84:417–426. 45. Izumi Y, Oyama T, Ikeda E, Kawamura M, Kobayashi K. The acute effects of transthoracic cryoablation on normal lung evaluated in a porcine model. Ann Thorac Surg 2005;79:318–322. 46. Cooper IS, Samra K, Wisniewska K. Effects of freezing on major arteries. Stroke 1971;2:471–482. 47. Ladd AP, Rescorla FJ, Baust JG, et al. Cryosurgical effects on growing vessels. Am Surg 1999;65:677–682. 48. Denny-Brown D, Adams RD, Brenner C, Doherty MM. The pathology of injury to nerve induced by cold. J Neuropathol Exp Neurol 1945;4:305–323. 49. Whittaker DK. Degeneration and regeneration of nerves following cryosurgery. Br J Exp Pathol 1974;55:595. 50. Kawasaki R, Gauri A, Elmouchi D, Duggal M, Bhan A. Atrioesophageal fistula complicating cryoballoon pulmonary vein isolation for paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2014;XX:XX–XX. 51. Andrade JG, Dubuc M, Ferreira J, et al. Histopathology of cryoballoon ablation‐ induced phrenic nerve injury. J Cardiovasc Electrophysiol 2014;25:187–194. 52. Mondésert B, Andrade JG, Khairy P, et al. Clinical experience with a novel electromyographic approach to preventing phrenic nerve injury during cryoballoon ablation in atrial fibrillation. Circ Arrhythm Electrophysiol 2014;XX:XX– XX. 53. Chierchia G-B, Di Giovanni G, Sieira-Moret J, et al. Initial experience of threeminute freeze cycles using the second-generation cryoballoon ablation: acute and short-term procedural outcomes. J Interv Card Electrophysiol 2014;39:145–151. 54. Andrade JG, Dubuc M, Guerra PG, et al. Pulmonary vein isolation using a second‐generation cryoballoon catheter: a randomized comparison of ablation duration and method of deflation. J Cardiovasc Electrophysiol 2013;24:692–698. 55. Lim HW, Cogert GA, Cameron CS, et al. Atrioesophageal fistula during cryoballoon ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014;25: 208–213. 56. Avitall B, Horbal P, Vance D, Laske T. A new cryo balloon efficacy and safety monitoring: distal balloon impedance and temperature recording. Paper presented at Heart Rhythm Society 35th Annual Scientific Sessions; XXXX XX, 2014; San Francisco, CA. Abstract XX.
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