Transcatheter Cryoablation Part I: Preclinical Experience

The concept of cooling to treat medical disorders dates back to the ancient Egyptian Edwin Smith Papyrus on surgical trauma, written between 3000 and 2500 B.C. Hypothermic therapy was recommended for abscesses that were “oily, like fluid under thy hand, which produce some clamminess of the surface.”1 Modern forms of cryothermal tissue ablation have been used surgically for decades in numerous organ systems and for various pathologies. Unlike heat that destroys cells by coagulation and tissue necrosis with potential for thrombus formation and aneurysmal dilatation, cryoablation involves a distinct pathophysiological process. As such, it carries a unique safety and efficacy profile. While not novel as an energy modality, harnessing cryoenergy into a steerable transcatheter format represents a more recent landmark in the history of arrhythmia therapy. In Part I of this two-part series, we will focus on the body of knowledge underlying the development of a transcatheter cryoablation system. Pertinent features related to biophysics and mechanisms of cryothermal tissue injury will be highlighted, key historical developments considered, and experience gained from cryosurgery with hand-held probes summarized. Preclinical studies with transcatheter cryoablation will be detailed, setting the framework for human applications. Part II of this series will review the current state of knowledge regarding clinical experience with transcatheter cryoablation. The objective of cryoablation is to freeze tissue in a discrete and focused fashion to destroy cells in a targeted area. Simplifying complex mechanisms of cellular injury, tissue damage involves freezing and thawing, hemorrhage and inflammation, replacement fibrosis, and apoptosis.2 Hypothermia causes cardiomyocytes to become less fluid as metabolism slows, ion pumps lose transport capabilities, and intracellular pH becomes more acidic.3 These effects are entirely transient, provided that the duration of nonfreezing cooling temperatures does not exceed a few minutes. Indeed, the briefer the exposure to a hypothermic insult, the more rapidly cells recover. As a clinical correlate, this characteristic of cryoenergy permits functional assessment of putative ablation sites (i.e., cryomapping) without cellular destruction. In contrast, the hallmark of permanent tissue injury is ice formation. As cells are rapidly cooled to freezing temperatures, ice crystals form within the extracellular matrix and then intracellularly as well.4 The size of ice crystals and their density is dependent on proximity to the cryoenergy source, the local tissue temperature achieved, and the rate of freezing. While the crystals do not characteristically destroy cell membranes, they compress and deform nuclei and cytoplasmic components.5, 6 Mitochondria are particularly sensitive to ice crystals and are the first structures to suffer irreversible damage.7-9 Upon completion of freezing, the tissue passively returns to body temperature, resulting in a “thawing effect.” This is an important component of cryoablation, as rewarming causes intracellular crystals to enlarge and fuse into larger masses that extend cellular destruction.3, 4, 10, 11 Hemorrhage12 and inflammation6 characterize the second later phase of cryoablation.2 In what has been termed a “solution effect,” water migrates out of myocardial cells to reestablish the osmotic equilibrium that was disturbed by ice crystals. In effect, this increases the intracellular solute concentration to a hyperosmotic state that may damage cell membranes.10 As the microcirculation is restored to previously frozen tissue, edema ensues. The fluid traverses damaged microvascular endothelial cells, resulting in ischemic necrosis. In the final phase of cryoinjury, replacement fibrosis and apoptosis of cells near the periphery of frozen tissue give rise to a mature lesion within weeks.13 Typically, these lesions are well circumscribed, with distinct borders, dense areas of fibrotic tissue, contraction band necrosis, and a conserved tissue matrix, including endothelial cell layers.14 Cryosurgical devices cooled by liquid nitrogen were introduced in the early 1960s.15 This technology was extended to treat a wide spectrum of pathologies including dermatologic, prostatic, hepatic, gynecologic, ophthalmologic, neurosurgical, and oncologic disorders.3, 16-18 Preceding these widespread applications, Hass19 and Taylor et al.20 first described predictable controlled myocardial lesions with cryoenergy using carbon dioxide as a refrigerant. Initial descriptions of tissue characteristics remain valid today. Notably, lesions were described as homogeneous and sharply demarcated with preserved ultrastructural integrity. These attributes, with absence of aneurysmal dilation or rupture, were attributed to the remarkable resilience of collagen and fibroblasts to hypothermal injury.21 Table I summarizes key historical landmarks in the development of a transvenous cryoablation system for cardiac arrhythmias.15, 19, 21-25 It was in 1964 that Lister et al.22 first described the application of cryoenergy to the cardiac conduction tissue by suturing a 4-mm “U”-shaped silver tube near the bundle of His. This may be considered the origin of “cryomapping” as well. Sinus node function was inhibited by cooling with an alcohol and carbon dioxide mixture at −10°C to −20°C. At the atrioventricular (AV) node, PR interval prolongation occurred at −45°C and progressed to high-grade AV block. Normal AV conduction resumed almost instantaneously upon discontinuation of cooling. In 1977, Harrison et al.21 introduced cryosurgery with hand-held bipolar electrode probes, first in 20 dogs with AV nodal ablation followed by three patients with refractory supraventricular tachycardia. Under cardiopulmonary bypass, complete but reversible AV block was achieved in all patients when the temperature of the nitrous oxide probe was lowered to 0°C at the His bundle site. Permanent complete AV block resulted when the temperature was further lowered to −60°C for 90 to 120 seconds and at least two consecutive freeze/thaw cycles were delivered. Longer-term follow-up on a larger series was later reported, with AV block achieved successfully in 17 of 22 patients.26 Additional studies reported similar results.27-29 Approaches not requiring extracorporeal bypass were later devised.28, 30, 31 Bredikis28 described a technique consisting of two atriotomy incisions; one for digital palpation and the second for the cryoprobe. Positioning of the cryoprobe was guided by recording electrodes, cryomapping, and/or pressure-induced AV block. Using this method, complete AV block was achieved in 85% of 34 patients28 and 92% of 72 patients.30 Louagie et al.31 proposed an alternative epicardial approach via the right coronary fossa. Gallagher and coworkers32 reported the first two cases of successful cryosurgical accessory pathway ablation in 1977. One pathway was concealed and paraseptal and the second manifest and left-sided. Several case series followed,33-38 with the largest reporting an epicardial approach in 105 consecutive patients with Wolff-Parkinson-White syndrome (74 left lateral, 23 paraseptal, and 11 right ventricular free wall).36 The AV fat pat was mobilized and dissected and the accessory pathway exposed and cryoablated. All but one patient had acutely successful ablation. However, four required repeat interventions for what the authors believed were subendocardial pathways protected by warming effects of circulating blood. A different approach to ablation was described in a series of 21 patients.34 Left-sided pathways were targeted by cryoprobes designed to enter the coronary sinus, obviating the need for extracorporeal bypass. Overall, 19 of 21 patients were successfully treated. Acute rupture of the coronary sinus occurred in two instances and required surgical ligation. In 1978, Gallagher et al.39 cryosurgically ablated a pharmacologically resistant ventricular tachycardia focus in the anterior right ventricular free wall with three 90-second applications at −60°C. A second case was reported the following year.40 Cryosurgery has since become a recognized treatment for selected patients with refractory ventricular arrhythmias,16, 27, 41-44 often as an adjunct to more extensive surgery including aneurysmectomy, subendocardial resection, encircling endocardial ventriculotomy, coronary artery bypass grafting, and valvar replacement.2 To date, no prospective studies have compared cryosurgical efficacy and safety to other treatment modalities. With cryosurgery alone, Caceres et al.45 and others46 reported 93% event-free follow-up in patients with refractory ventricular tachycardia. These results compare favorably to historical cohorts that used other surgical modalities for ventricular tachycardia.46-48 Surgical cryoablation has also been described for less common arrhythmias including nodoventricular tachycardia,49 sinoatrial reentrant tachycardia,50 ventricular disabling bigeminy,51 bidirectional bundle branch reentry tachycardia,52 and fetal malignant tachyarrhythmias.53 It has also been used in AV nodal reentrant tachycardia and other arrhythmias with rapid AV conduction with the shared objective of slowing but preserving nodal conduction.54-56 Holman et al.57 successfully eliminated dual AV nodal physiology in three dogs. Cox et al.58 later applied hand-held cryoprobes to eight patients with drug-refractory AV nodal reentry tachycardia. All patients were successfully treated without requiring permanent pacing, although right bundle-branch block was induced in three cases. Animal studies of cryosurgical ablation have characterized lesions and demonstrated that dimensions relate to temperature of the cryoprobe and myocardium, probe diameter in contact with cardiac tissue, exposure time, and number of freeze/thaw cycles.12, 59-61 Longer duration of freezing and lower temperatures produce larger lesions, although a plateau is reached within five minutes.6, 10 Double freeze/thaw cycles generate larger lesions than single applications of longer duration.62, 63 Such parameters could be varied to produce predictable lesions.11, 61 As illustrated in Figure 1, cardiac cryosurgery is still used today, although less commonly. Insights gained from the cryosurgical experience contributed invaluably to conceptualizing the modern transcatheter cryoablation system. Surgical ablation with a cryoprobe. Gillette et al. reported the first animal study using a transvenous cryocatheter in 1991.23 In five miniature swine, complete AV block was produced with an 11-French cryocatheter cooled by pressurized nitrous oxide. Cryothermia was applied for three minutes and repeated up to three times. Four of the five pigs remained in AV block for one hour, while one recovered partially with 2:1 AV conduction. Histologically, acute lesions were sharply delineated and hemorrhagic. In a chronic study of eight swine, successive three-minute cryoapplications were delivered to the AV junction at −60°C via 8 or 11-French cryocatheters.64 Long-term AV block was maintained in five of eight animals. At six weeks, well-defined dense lesions were noted histologically, free of inflammation or thrombus formation. Although feasibility of transcatheter cryolesion formation was demonstrated, limited success was attributed to lack of steerability and recording electrodes. Cryocatheter placement required using a second catheter to record local signals. Transcatheter cryoablation was revived several years later, ultimately leading to clinical use. We reported the first animal experiment using a steerable cryocatheter with integrated recording and pacing electrodes in 1998.24 Right and left ventricular lesions were created in six dogs using a 9-French catheter with a 4-mm electrode tip and Halocarbon 502 (Freon®) as a refrigerant. Cryomapping (i.e., reversible ice mapping) of the AV node was demonstrated by sequentially applying lower temperatures to the AV nodal junction. When high-degree AV block or >50% PR prolongation was achieved, the cryoapplication was interrupted. In all cases, 1:1 AV conduction resumed within seconds. No lesion was identifiable on gross and microscopic histopathology. In a further study of cryomapping with more detailed electrophysiological measurements, reversible AV nodal effects were achieved in seven of eight dogs at a mean temperature of −40°C.13 Parameters including sinus cycle length, atrial-His (AH) interval, His ventricular (HV) interval, Wenckebach cycle length, and AV node effective refractory periods, measured before, 20 minutes, 60 minutes, and up to 56 days after cryomapping were not significantly different. Chronic cryoablation lesions, created at a mean temperature −55°C, were later characterized in nine mongrel dogs sacrificed three and six weeks after ablation.13 Histologically, well-demarcated ultrastructurally intact lesions devoid of thrombus were observed. Similar results were obtained with 8.5-French cryocatheters in six dogs65 and seven pigs.66 To better define optimal cryoablation parameters, single versus double freeze/thaw cycles were compared at the lowest temperature (−50°C to −55°C) permitted by the system at the time.13 These lesions were applied to sites where cryomapping (>−40°C) had been successful. Permanent chronic AV block was achieved in all six dogs with double freeze/thaw cycles compared to only one of six with single freeze/thaw cycles. Consonant with this observation, intralesion residual strands of viable tissue were noted histologically with single but not double freeze/thaw cycles. Thus, at these temperature and freezing rates, double cycles were more effective than single ones for AV nodal ablation. Larger lesions with more extensive tissue injury have been consistently reported with double freeze/thaw cycles applied to other organs as well.3, 17 However, later iterations of the transcatheter cryoablation system permitted lower attainable temperatures (−80°C) and faster cooling rates when nitrous oxide was used as a refrigerant. Cryobiology experts have since refrained from systematically recommending double freeze/thaw cycles. Preclinical studies contributed importantly to our understanding of the impact of cooling rate and catheter tip-temperature on tissue effects.3, 13, 16, 24, 27 Cooling first occurs at the distal catheter tip in contact with endocardial tissue. Freezing then extends radially into the tissues, establishing a temperature gradient. The lowest temperature and fastest freezing rate is generated at the point of contact, with slower tissue cooling rates more peripherally. Of importance, as distant tissue achieves a temperature in the order of −20°C to −30°C, a “dynamic cryomap” is obtained. Reversible local tissue effects precede cell death. A clinical corollary is that despite an initial reassuring cryomap, vigilance for perinodal substrates is mandated as the iceball continues to expand during cryoablation and the centrifugal temperature gradient further extends into the tissue.12, 13, 24, 60, 61 The first cryosurgical device developed by Cooper in 196315 produced cooling by means of a liquid to gas phase change in nitrogen. Principles such as the Joule-Thompson effect (cooling by expansion of a compressed gas after passage through a needle valve) and Peltier effect (thermoelectric cooling) have been incorporated into the design of cryoprobes.11, 16 A variety of devices were developed using several methods of refrigeration and numerous cryogens including nitrogen, nitrous oxide, solid carbon dioxide, argon, and several fluorinated hydrocarbons.3 We initially described a transvenous cryocatheter system that used Halocarbon 502 (Freon®) as a refrigerant (Cryocath Technologies Inc., Montreal, Canada)24 (Fig. 2). The refrigerant was later changed to Genetron® AZ-2067 and then nitrous oxide,14 used currently. The cryocatheter essentially consists of a hollow shaft with a closed distal end containing a cooling electrode tip and three proximal ring electrodes for recording and pacing. A central console that contains the refrigerant fluid releases the cryogen under pressure. The cooling liquid travels through the inner delivery lumen to the distal electrode that is maintained under vacuum. At the cryocatheter tip, the liquid cryogen boils. This accelerated liquid-to-gas phase change results in rapid cooling of the distal tip. The gas is then conducted away from the catheter tip via a vacuum return lumen and back to the console where it is collected and restored to its liquid state. Temperature is recorded at the distal tip by an integrated thermocouple device. Catheter cryoablation system. Reproduced with permission from Dubuc et al.,24 Please see text for a detailed description of the various components. Several theoretical advantages are noted when cryoablation is compared to radiofrequency (RF) energy, as summarized in Table II. With hypothermia generated at the distal cooling electrode, the catheter adheres to tissue affording greater catheter stability. Metaphorically, this has been likened to the adhesiveness of a wet tongue contacting a frozen the catheter is on to may be during cryoablation without for catheter that during and with are This may be particularly the is at a where contact is to or ablation of tissue is It also permits ablation to be during tachycardia without the of catheter upon arrhythmia In a study of 22 mongrel and cryolesion dimensions created by were Overall, lesions were of greater 20 with significantly larger Notably, no in lesion was to 6 Histologically, were more homogeneous with and from underlying myocardium, as in Figure In contrast, lesions had more Thus, more focused lesions were noted with cryoablation. may be less with damaged but viable cells are more to characteristics one after cryoablation when the homogeneous cryolesion with a from intact myocardium, and absence of of the lesion from catheter pressure. dimensions created by versus were in but greater in and temperatures were with a temperature resulted in a lesion ventricular lesions were than their and all lesions were It was demonstrated that larger lesions could be created by the temperature or the of the catheter tip in contact with A more recent in experiment conducted on ventricular that lesion dimensions and tissue temperatures were by warming as controlled by electrode contact electrode and catheter refrigerant Catheter size the effect of electrode temperature on lesion To compare of and cryoenergy we conducted a study ablation lesions in 22 dogs at right right and left ventricular energy was five more than cryoablation by seven days after ablation. thrombus was significantly greater with compared to cryoablation the of tissue injury was with thrombus This was where lesion dimensions were not of thrombus It was that this the that intact tissue with endothelial cell was maintained with In the the to of the freezing was considered a that in Indeed, of the freeze/thaw cycle and frozen tissue contributed to rapid in and The to formation by means was demonstrated in transcatheter cryoablation Using a on a was in six dogs double freeze/thaw cycles. contact was by and were to ice ice formation as a density with a and No of was during cryoablation. The size of the ice was to enlarge during the first three minutes of the freezing cycle and remain These the current to the cryoablation to four minutes. Several have been regarding ablation near the and within the coronary sinus ablation the and may fibrosis and and are potential However, the is coronary artery The and/or right coronary artery may in proximity to the arrhythmia the AV nodal artery near the of the coronary ablation may damage this Preclinical studies a lower of coronary artery following cryoablation compared to ablation. In an study in to within the and distal coronary sinus, no coronary was and coronary artery and were In a et demonstrated that cryoablation in the coronary sinus within of the left artery produced myocardial lesions similar to energy but with a of coronary artery Histologically, of the to energy had coronary artery damage compared to with cryoablation. The of and clinical experience with surgical cryoablation the for transcatheter cryoablation. potential advantages were demonstrated in including catheter for thrombus temperature for reversible and delineated focused cryoablation systems were as catheter were to the mechanisms and to more rapid cooling and lower a the initial 9-French steerable catheter with cooling and a temperature of was into the modern with rapid cooling and temperatures In transcatheter cryoablation was first applied to This was in by a in and