Atrial fibrillation ablation – from surgery to radiofrequency, cryo and beyond

Contact address: Dan Musat, MD, 970 Linwood Avenue, Paramus, 07652, NJ. E-mail: musada@valleyhealth.com 1 Department of Cardiovascular Services, Snyder Center for Comprehensive Atrial Fibrillation, Valley Health System, Paramus, NJ success of AF ablation is signifi cantly improved with control of comorbidities, like diabetes, hypertension, hyperlipidemia, and lifestyle modifi cations including evaluation and treatment of sleep apnea, weight management (with a goal of ≥10% of weight loss and a BMI below 27 kg/m2), increase in fi tness and alcohol use reduction or cessation, as well as smoking cessation1.


SURGICAL ATRIAL FIBRILLATION ABLATION
The race for AF treatment has started since early 1980's with cardiac surgeons leading the way. Although the AF pathophysiology was not very well understood at that time, the goal was to slice the atria to decrease the area where AF wavelets could form reentrant circuits and to isolate the "hollow structures" in the atria (cava veins, pulmonary veins and left atrial appendage) 14 . Dr. James Cox was the pioneer in development of the technique for Cox-Maze procedure, which involves multiple cut and sew lesions of the left and right atrium. The procedure went through a series of iterations and evolved in widely used Cox-MAZE IV 15,16 (Figure 1), using cut and sew lesions, along with radiofrequency and cryo lesions, to create electrical isolation of the pulmonary veins and posterior wall, as well as left atrial appendage excision. Long-term results have been reported over the years in multiple series of hundreds of patients 17 , one of the largest being a series by Khiabani et al. which reported outcomes of 853 patients undergoing Cox-Maze IV procedure, 60% having non-paroxysmal AF and about a quarter who failed a previous catheter ablation. They showed freedom from atrial tachyarrhythmias, off antiarrhythmic Atrial fi brillation (AF) is the most common sustained cardiac arrhythmia in the current era, affecting 43.6 million people worldwide in 2016 (about 0.5% of global population) 1 ; a more than 30% increase over the past 20 years 2 . Future predictions suggest an worldwide increase in AF burden of more than 60% by 2050. 2 This imposes a tremendous burden on healthcare systems worldwide with an estimated annual cost up to $ 26 billion in USA 3 and € 3.3 billion in Europe 4 .
AF has a progressive natural history, from paroxysmal AF (episodes lasting less than 7 days and terminated either spontaneously or after interventions), to persistent AF (episodes lasting more than 7 days), and eventually to permanent AF if no efforts are made to restore and maintain sinus rhythm 1 . AF management strategies include either a rate or a rhythm control, depending on the symptoms and patient preference, using medical treatment such as AV node blocking agents or antiarrhythmic medication or a more invasive approach with surgical ablation, percutaneous catheter ablation or a hybrid approach.
The effi cacy of any intervention for AF is judged by the absence of any recurrence of AF lasting 30 seconds or longer, an endpoint chosen by EHRA/ACC/ AHA/HRS inter-societal convention 1,5,6 . This arbitrary, short duration endpoint has sparked many controversies 7,8 , however it has been the gauge by which any new techniques, tools and technologies have been evaluated throughout the years.
Multiple randomized trials [9][10][11][12] , non-randomized series and meta-analyses have demonstrated that AF catheter ablation portends a superior success to antiarrhythmic medication for maintaining of sinus rhythm and preventing AF recurrences 13 . The long term at one year [28][29][30][31] . However, these approaches were plagued by long procedural and fl uoroscopy duration and high complication rates up to 30 % 31 .
The revolutionary discovery in 1997 by Dr. Michel Haissaguerre that the impulses responsible for starting AF originate in the pulmonary veins ( Figure 2) has opened the current era for development of minimally invasive techniques and technologies for catheter based treatment of AF 32,33 . In the series of 45 patients, he reported that 94% of the ectopic foci starting AF were detected in the pulmonary veins (PV) 32 .
Catheter ablation has become the method of choice for rhythm control strategy of symptomatic paroxysmal or persistent AF, currently recommended either as fi rst choice or after failure of an antiarrhythmic medication 1 .
During early experience, catheter manipulation and positioning guided only by fl uoroscopy and contrast angiograms resulted in high fl uoroscopy time and radiation exposure. In the late 1990's the non-fl uoroscopy tri-dimensional (3D) mapping systems started their development 34 . They are providing the possibility of reconstructing intracardiac and vascular anatomy, are capable of merging with pre-procedural cardiac imaging as CT or MRI, and most important they provide electro-anatomic activation and substrate maps with the ability to visualize the mapping and ablation catheters. Over the years, with technological advances, the 3D maps have become extremely accurate, currently being the standard of care for vast majority of ablations, with substantial decrease in fl uoroscopy time and radiation exposure and an increase in success and safety of ablations 35 . In association with intracardiac echocardiogram, feedback about tissue contact provided by the newer ablation catheters, an increasing number of centers nowadays are performing non-fl uoroscopic AF catheter ablations [36][37][38] .
The initial experience with ablation of the induced pulmonary vein trigger foci inside the veins has encountered a signifi cant occurrence in pulmonary vein stenosis ranging from 3-42%, with high AF recurrence rates 32,39,40 . Recognition of a high prevalence, in up to 69% of patients, of multiple arrhythmogenic veins led to an empiric all pulmonary vein isolation (PVI) approach 40 . This approach addresses the triggers for AF initiation, by disconnecting electrically the veins from the left atrium, as well as neuro-modulation factors by affecting the ganglionic plexi usually found at the antrum of pulmonary veins 41,42 . It has become the cornerstone of the AF ablation, the most popular medication, of 84%, 71% and 61% at 1 year, 5 years and 10 years respectively 16 . Although the long-term results are very attractive, this invasive AF treatment option as standalone procedure is not appealing, so most of the times is performed as concomitant procedure at the time of open-heart surgery for other reasons. The associated risks are those of open heart surgeries with a perioperative mortality of 0.74% -3.3% and overall complications rates ranging from 3.2 to 21% with a higher need for pacemaker therapy, ranging from 1.03% up to 12% in different series [16][17][18][19][20] . This approach in long term follow-up, retrospective analyses, have suggested an improved mortality and lower stroke rates 17,18,21 . Advances in the ablation tools and technologies led to development of minimally invasive surgical techniques for off pump epicardial or hybrid epicardial/endocardial ablation (Figure 1), however the results suggest a lower long term success rate 62-83% 20,22 , likely due to inferior lesion durability, and a higher complication rate, mostly conversion to sternotomy and bleeding complications 20,22,23 . Improvement of the convergent hybrid procedure technique led to a signifi cant decline in complication, and with epicardial posterior wall isolation, endocardial PVI and more recently left atrial appendage exclusion, offer a more appealing mini-invasive approach mimicking the Cox-Maze IV 22 , especially in patients with persistent or longstanding persistent AF. Overall, surgical AF ablation has shown to have a higher effi cacy than endocardial catheter AF ablation in long term maintenance of sinus rhythm 22,24 .

MINIMALLY INVASIVE ATRIAL FIBRILLATION CATHETER ABLATION
The era for less invasive ablation procedures started with introduction of catheter based ablation by Dr. Melvin Scheinman in 1982, born out as necessity for a treatment solution in patients who failed medical treatment and were not candidates for surgical approach. He initially used high-energy (300J -500J) direct current shocks to ablate the fast AV nodal pathway for treatment of supraventricular tachycardia 25,26 and to control irregular cardiac rhythm in patients with AF ( Figure 2). This transitioned into unipolar radiofrequency ablation, introduced by SK Huang in 1987 27 . The new technology provided the tools to attempt of reproducing the surgical ablation with a more appealing mini invasive approach. There were several series published that have used various linear ablation approaches in the left and/or right atrium, with success ranging from 33-79% in maintaining sinus rhythm (>100°C) would result in charring (deposits of denaturated plasma proteins) on the tip of the catheter leading to impedance rises, ineffi cient RF delivery and potential for thrombus formation and embolization 43,46 . These shortfalls of non-irrigated catheters led to development of the open irrigation catheters that currently are the norm for AF ablation. During RF delivery, the tip of the ablation catheter is constantly fl ushed via small ports with normal saline. This provides the ability to deliver higher power without increase in impedance or char formation, resulting in deeper, transmural lesions. However, the local tissue temperature feedback is lost, leading to possible complications due to excessive tissue heating and "steam pops" from boiling fl uids inside the tissues 45, 46 .
Although the success of AF ablations improved 47 with open irrigation catheters, long term results of AF ablations were far from perfect and it was recognized that the Achile's heel of RF ablation remains the inability to provide effi cient and durable lesions, with up to 70% of pulmonary vein reconnections 1, 48 . Surrogate markers, as baseline impedance, impedance change, catheter position on reconstructed 3D maps proved to be inadequate 49,50 . Therefore, the efforts have focused to develop the tools for better evaluation of catheter stability and contact to the tissue during RF application, to assure transmural and contiguous lesions. The need to provide catheter-tissue contact feedback to the operator during RF application, led to development of contact force (CF) catheters. Two different contact force technologies have emerged. One platform uses a small spring that connects the ablation tip electrode to the catheter shaft, and translates the degree of this spring microdefl ections into CF (Thermocool Smartouch CF, Biosense Webster Inc., Diamond Bar, California, USA). The other platform uses three optical fi bers to convert the microdeformation of a deformable body inside the catheter tip into CF (TactiCath, Endosense/St Jude Medical, St Paul, Minnesota, USA). In TactiCath Contact Force Ablation Catheter Study (TOCCATA) Study and subsequent analyses 49,51,52 it was demonstrated that a CF target of >10 g provides an adequate lesion, with 100% of AF recurrence when the RF lesions were applied with CF <10 g and 20% AF recurrence when lesions were performed with a CF ≥20 g 51 . There was a wide variability in CF between the operators, with higher success when higher CF was applied consistently 51,52 and good stability of the catheter 48,53 . Similar fi ndings were reported in SMART-AF trial 50 using Thermocool approaches being segmental ostial ablation of the muscle sleeve connections and linear lesions around the antrum pulmonary veins (wide area circumferential ablation (WACA)), using either point-by-point radiofrequency applications or single-shot solutions1. Various types of energy have been considered over time for PVI, currently widely used being radiofrequency and cryothermal energies, with newer ones as pulse field electroporation and ultra-low cryothermal energy being in the early stages of development.

RADIOFREQUENCY ABLATION
Radiofrequency (RF) has been the fi rst and it still remains the preferred type of energy used for AF ablation. RF energy is delivered in a unipolar fashion using alternative current, at a frequency of about 550 kHz, between the tip of the ablation catheter inside the heart and a dispersive grounding pad on the surface of the skin 43 . The lesion is created by thermal destruction of the tissue through resistive heating at the site of contact of the catheter to the tissue surface (up to 1 mm deep) and via passive conductive heating of the deeper tissue from the superfi cial layers 43,44 . In order to obtain an adequate lesion depth, due to low conductivity of the heat in the myocardial tissue, the RF application needs to be 20-60 sec long to reach maximal temperature inside the tissue and thermal equilibrium (constant heat fl ow from electrode to the tissue) to achieve the deepest lesion 45 . Operators have to be aware of "thermal latency" after RF delivery is stopped, as conductive heat continues to travel through the tissue and increase the temperature, thus possible affecting sensitive tissues (AV node area, esophageal tissue) 45 . A temperature above 50°C results in irreversible damage of the myocardial tissue due to coagulation and destruction of the cells and structural network 43,46 . Various factors affect the lesion size -greater tissue contact and force of contact, larger catheter size, higher power, longer duration and higher electrode temperature lead to larger and deeper lesions 43 .

POINT-BY POINT RADIOFREQUENCY ABLATION
The fi rst type of catheter used for AF ablation was non-irrigated and as data started to accumulate it was clear this was not an ideal tool, creating non-transmural lesions, associated with high recurrence rates of AF due to PV -left atrium (LA) reconnections 47 . In addition, high temperatures at the tissue contact lation (93.4% vs. 62.9%, P < 0.001) and lower rates of acute PV reconnections (18.0% vs 35.0%; P = 0.006). In follow-up, atrial arrhythmia recurrence was also signifi cantly lower in AI compared to non-AI catheter ablation (11.8% vs. 24.9%, P = 0.0003).
Besides the lesion size and depth, for point-bypoint ablation techniques, lesion contiguity has been recognized to play an important role for PV reconnections. When an interlesion target was ≤6 mm, in the 'CLOSE'-protocol study, the incidence of acute, adenosine proof isolation, was higher than conventional AI guided ablation (97% vs 82% p < 0.001) 61 . Freedom from atrial tachyarrhythmias at 12 months after single-procedure was 94% in 'CLOSE' vs. 80% in conventional group (P < 0.05). The vast majority of reconnections at repeat ablations were associated with either interlesion distance >6 mm and/or AI <400/550 (100% vs. 83%, P = 0.99 between 'CLOSE' and conventional groups respectively).
Other innovations in lesion optimization were introduced with Boston Scientifi c IntellaNav MIFI™ Open-Irrigated catheter (Boston Scientifi c, Marlborough, MA, USA) which has in its tip 3 mini-electrodes capable of providing local bipolar electrograms and in conjunction with the 3D RHYTHMIA HDx™ (Boston Scientifi c, Marlborough, MA, USA) mapping system offers local and real time information about lesion formation. With ablation, mini-electrodes EGMs show a more substantial reduction in local amplitude compared to common bi-poles. Mini-electrode guided ablation, to maximal EGM attenuation, results in 91% transmural lesions (similar to standard 60 seconds ablation) but with a signifi cant reduction in ablation time (23.4 ± 7.8 seconds) and potentially avoiding extracardiac inju-ries64. This has improved further with the introduction of DirectSense™ (Boston Scientifi c, Marlborough, MA, USA) technology, capable of measuring the local tissue impedance with a superior identifi cation of type of local tissue and a much better correlation of local impedance change with lesion formation when compared with transthoracic impedance [65][66][67] . The technology is based on a non-stimulatory alternating current (5.0 A at 14.5 kHz) delivered between the tip and the proximal ring to create a local potential fi eld, with the mini-electrodes within the tip measuring potential field distortions caused by nearby cardiac structures or contact with high-resistivity myocardium [65][66][67] . In CHA-RISMA pilot trial 65 a local impedance decrease during RF application of ≥15 Ω was strongly associated with an effective and durable lesion, irrespective of the ba-Smartouch catheter with improved ablation success when the CF >18 g and when the operators maintained ≥80% of the time CF in the pre-specifi ed range, suggesting that besides the CF, stability plays an important role for durable lesion formation. Safety concerns were raised for both catheters when a CF >40 g, with increase in the incidence of tamponade 50,51 .
Although the initial data was encouraging, with observational and some randomized studies suggesting a signifi cant improvement in the success of AF ablations (71% vs 61%, especially for paroxysmal AF), decrease in the procedural, fl uoroscopy and in RF times [54][55][56][57] , the initial enthusiasm vanished as more data accumulated. A systematic review and meta-analysis on almost 10,000 patients who were part of 26 observational and 9 randomized studies comparing CF ablation catheters with non-CF catheters showed that overall analysis of all the studies reproduced initial fi ndings. However, when the analysis was restricted to the randomized studies only, the benefi ts of CF-guided ablation in terms of safety, effi cacy, and procedural characteristics were no longer signifi cant 58 . This was thought to be in part due to participation in the trials of experimented operators, already vexed with catheters without CF feedback, as well as less experimented operators with high variation in adequate CF maintenance during RF applications 59 .
The race for better ablation tools with more effective and durable PV isolation has reached a new stage with the newest catheters and software capable of integrating multiple ablation variables to evaluate the effi cacy of ablation and tissue characteristics during RF application. Ablation index (AI) represents a novel marker of ablation lesion quality developed and integrated into the automated lesion tagging software (Vi-siTag) in the CARTO 3 3D electroanatomic mapping system (Biosense Webster, Inc, Diamond Bar, CA) that incorporates power, CF, and time, in a proprietary weighted formula and was found to accurately estimate ablation lesion size 60,61 . An AI value of more than 480-540 at the anterior and roof regions and 370-380 at the posterior regions were predictive of freedom from acute and long term reconnections respectively 60,62 . Currently accepted targets are 550 for anterior and 400 for posterior regions 60,61 . A metaanalysis comparing AI guided procedures with non-AI guided approach, in 2306 patients enrolled in eleven studies 63 , showed a signifi cant shorter procedural time (141.0 vs. 152.8 min, P = 0.01), shorter ablation time (21.8 vs. 32.0 min, P < 0.00001), higher fi rst-pass iso-generation, non-irrigated catheter. In Tailored Treatment of Permanent Atrial Fibrillation (TTOP-AF) trial at 6 months, 56% of ablated patients were free from AF, compared to 26% of those treated with antiarrhythmic therapy 74 . It yielded similar acute, medium and long-term AF ablation success rates as point-bypoint ablations, better in paroxysmal AF patients (median 74%, IQR 59-83%) than persistent AF patients (median 55% IQR 47-81%), with signifi cantly lower procedural and fl uoroscopy times [75][76][77][78] . However these results were overshadowed by concerns of increased symptomatic (2.9%) and asymptomatic cerebral thromboembolism (38-39%) rates compared to other ablation technologies [79][80][81] , and the catheter was not approved in US.
The second-generation PVAC GOLD (Medtronic, Minneapolis, MN, USA) catheter was redesigned to mitigate these risks. The platinum-iridium electrodes were replaced with gold, for enhanced thermal conductivity and power output, with greater passive cooling capacity. Other changes in shape included new 20°canted forward shape of circular array, for optimal contact, and reduction of number of electrodes to 9 electrodes, to eliminate electrode interference and reduce the risk of overheating observed between electrodes 1 and 10 (thought to be the possible cause of asymptomatic cerebral thromboembolism) 82 . In addition, the software upgrade included improved algorithms through the generator for more accurate electrode temperature detection. Gold AF registry included 1071 patients and showed a 12 months success rate of 78% (better in paroxysmal AF 82% than persistent AF 68%) and improved safety, reporting a total of 2.5% 82 compared with previously reported PVAC complications of 3.9% 76, and symptomatic ischemic cerebral embolism of 0.3% compared to 1.1-2.9% with PVAC 74,76 . However, despite updated technology several series still report a concerning high incidence of asymptomatic cerebral embolic events in up to 26% patients on vitamin K antagonists and 33% patients on direct anticoagulants, despite uninterrupted anticoagulation and high levels of anticoagulation during procedure 83 . Furthermore, a randomized trial of 70 patients showed a signifi cantly higher incidence of new cerebral lesion on post procedural MRI, 8/35 (23%) of patients ablated with PVAC Gold vs. 2/35 (6%) of patients ablated with ThermoCool (Biosense Webster, Inc. Diamond Bar, CA, USA) catheter 84 .
Following the same development path of point-bypoint ablation catheters, an open irrigated multi-elec-seline voltage of the site, with 91% atrial arrhythmia free at a mean follow-up of 404 ± 111 days. A local impedance decrease of more than 30 Ω has raised concerns for "steam-pops".
The ability for meaningful feedback about lesion formation using these new technologies has opened the appealing strategies of high power and short duration ablation, with shorter procedure and ablation times, better lesion formation and contiguity, with promising increased safety for extracardiac structures as well [68][69][70] . A new catheter, QDOT Micro catheter (Biosense Webster, Inc., Irvine, California) capable to deliver RF lesions with a 90W power showed promising results in the fi rst in humans' series of 52 patients with paroxysmal AF71. The high power RF was applied for 4 seconds per lesion, with 100% acute pulmonary vein isolation with study catheter and demonstrated good safety profi le with only 2 complications (1 pseudoaneurysm and 1 asymptomatic cerebral thromboembolism present on MRI at discharge). In follow-up, 94% of patients were in sinus rhythm at 3 months.
The long journey of RF ablation for AF has reached new heights in improved lesion formation and durability that resulted in incremental success rates of pulmonary vein isolation, linear circumferential being superior to ostial segmental ablations 72 , from 60-80% 58,72,73 freedom of recurrent atrial tachy-arrhythmias to high 80-90% with the circumferential ablation guided by newest technologies 61,63,65 . The safety of AF catheter ablation has improved over the years, a worldwide survey in 2010, that included almost 20,825 procedures in 16,309 patients, reported major complications in 4.5% of patients 73 (Table).

ONE-SHOT RADIOFREQUENCY ABLATION
Efforts to streamline the ablation procedure, decrease procedural time, increase reproducibility and assure contiguity of the lesions, led to the development of one shot ablation approach. Several tools for radiofrequency ablation became available including multielectrode and balloon catheters.
Multi-electrode ablation catheters have a circular shape with 9 or 10 electrodes, along with multichannel RF generator capable of simultaneously delivering duty-cycled energy, provide the ability to deliver unipolar or bipolar RF applications or combination of both to multiple electrodes at once. Multiple series have reported the results of ablations using PVAC ® (Medtronic Ablation Frontiers, Carlsbad, CA) a fi rst ents, evaluated the effi cacy and safety of the balloon in phase I and showed acute isolation using the balloon in 89% of pulmonary veins with 80% freedom from AF at 6 months 89 . In phase II, after device enhancements additional 81 patients were enrolled and acute PVI increased to 99.4%. There were no device related serious events at 30 days post-procedure. At 12 months, 78.1% of the patients (phase I and II of the trial) were free of atrial arrhythmias 90 .
The Globe is a globular array consisting of 16 ribs with 122 gold-plated fl at, non-irrigated electrodes, each of whom perform multiple functions including ablation, measurement of tissue contact and temperature using a sensor positioned directly behind the electrode, recording intracardiac electrograms as well as tissue stimulation. The catheter is capable of generation multiple maps, the FLOW and CONTACT maps providing continue information about contact with atrial tissue and creating anatomy, the VOLTA-GE and WAVE maps assessing voltage and electrical activation. Ablation can be performed using up to16-24 electrodes simultaneously with temperatures up to 65°C. The GLOBE AF trial enrolled 60 patients and acute isolation of 99.1% of the veins ablated 91 . In 34 patients, in whom "single-hot-shot" strategy was considered, ablation was applied with up to 24 electrodes and a temperature set point of up to 65°C, acute PVI was achieved in 100% veins. There were 2 pericardial tamponade related to transseptal puncture and catheter insertion in the left atrium. In 28 patients ablation had to be stopped due to esophageal temperature increase. At 12 months freedom from atrial tachyarrhyhtmias, off antiarrhythmic medication was 72.3%.

CRYO-ENERGY ABLATION
Cryo-energy ablation produces myocardial tissue damage by direct cellular injury with extreme cooling. There are 3 phases of cellular destruction with cryo energy: 1) the freeze/thaw phase, 2) the hemorrhagicinfl ammatory phase, and 3) the replacement fi brosis phase 43,92 . In the initial freeze/thaw phase the cryorefrigerant draws heat out of healthy tissue, progressive cooling leading to the formation of ice crystals initially extracellular, below -15°C and then intracellular as temperature falls below -40°C. The crystals cause cellular mechanical disruption, however the predominant mechanism of injury is biochemical, created by extracellular ice crystals hypertonic environment which attracts intracellular water. This leads to increase intracellular saline concentrations with reduction of trode catheter was developed: nMARQ™ (Biosense Webster, Inc. Diamond Bar, CA, USA) is an irrigated circular RF catheter visible and integrated with the CARTO system (Biosense Webster, Inc. Diamond Bar, CA, USA). The fi rst in humans experience was in March 2013, and the nMARQ™ catheter was recalled from clinical use in June 2015 due to safety concerns of high silent cerebral lesions (33%), high incidence of esophageal thermal injuries (33%) 85 and reporting of three deaths in a small study, of which two were confi rmed to be due to esophageal-atrial fi stula 75,86 . The success of ablation at one year in multiple small series was 66-87% freedom of atrial arrhythmias. A new prototype is currently under evaluation 75 .
Of note, a number of the series using multi-electrode catheters reported the need for focal RF ablation "touch-ups" in 2.7-5.7%, to achieve complete pulmonary vein isolation 75 .
The uncertainty of the multielectrode catheters future, with the lessons learned from cryoballoon therapies, radiofrequency balloon based technology was developed for one-shot ablation. To date there are 3 systems available: Heliostar balloon (Biosense Webster, Diamond Bar, CA, USA), Luminize balloon (Boston Scientifi c, Marlborough, MA, USA), and Globe catheter (Kardium, Burnaby, Canada).
The Heliostar compliant balloon has 10 circular oriented, irrigated electrodes, on the surface that can be used for visualization, stimulation, recording and ablation in conjunction with the Carto 3 system 87 . The balloon delivers RF energy directly through the electrodes, forming a continuous circular ablation lesion around the PV ostia. In RADIANCE, the fi rst in human trial, acute success was 100% pulmonary veins isolation using the balloon, with 4.6% acute reconnections after adenosine injection, successfully re-isolated with the balloon 88 . There was only one primary adverse event, right phrenic nerve injury. At 12 months, the freedom from AF was 76% off antiarrhythmic medication 87 . Currently the Safety and Effectiveness Evaluation of the Multi-Electrode Radiofrequency Balloon Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation (STELLAR) trial is conducted (Clini-calTrials.gov Identifi er: NCT03683030) with expected completion in April 2022.
The Luminize balloon has 12 equatorial and 6 distal irrigated electrodes with advantage of direct visualization of the endocardial structures with 4 cameras and LED illumination, for assessment of tissue contact. The AF-FICIENT fi rst in-human trial enrolled 18 pati-plications related to the catheter were 4 cases (7%) of right phrenic nerve injury (PNI) with cryo application at the right superior pulmonary vein, 2 of them recovered during the procedure, one at 3 months and one persisted at 6 months.
The fi rst randomized trial comparing cryoballoon ablation to AAD therapy was the Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP-AF) trial, and enrolled 245 patients with paroxysmal AF, who have failed 1.2 antiarrhythmics, with a 2:1 randomization to CB based PV isolation (n=163) versus AAD therapy (n=82)9. Acute PVI by the CB only, was achieved in 91% of participants, and success increased to 98.2% with additional focal cryoablation. A repeat procedure within the 3-month blanking period was performed in 19% of the patients. At 12 months of follow-up, 69.9% of the CB group (114/163) vs. 7.3% of the AAD group (6/82) were free of recurrent AF (p<0.001).
An improved, second CB (CB2) generation and a third CB generation (with a shorter tip), has eight jets directed towards the front hemisphere, delivering a more uniform cooling energy to the front of the CB. This upgrade has shown to improve the success rates at 1 year to 84% arrhythmia free survival off antiarrhythmic medication compared to 64-66% with fi rst generation CB (CB1) 94,95 , with decrease in procedural time, fl uoroscopy and increased rate of isolation with fi rst application. Compared to point-by-point radiofrequency PV isolation CB ablation has proven to be non-inferior in FIRE AND ICE trial, which randomized in 1:1 fashion 762 patients to either ablation strategy. Arrhythmia recurrence was seen in 35% of patients treated with CB1 and CB2 and 36% of patients treated with RF ablation (HR 0.96, CI 0.76-1.22, p < 0.001 for non-inferiority) 96 . The complication rate was similar for both strategies, however with higher PNI in CB arm, seen in 10 (2.7%) patients at discharge, however only 1 (0.3%) patient still had PNI at one year. Long term results of CB2, up to 3 years, were reported in STOP-AF PAS (post approval study), which enrolled 344 patients with paroxysmal AF 97 . Acute PVI success was 99.3%, using 28 mm CB in 89% of patients, 23 mm CB in 8.4% of patients and both in 2.6% of patients. Additional focal ablation using either cryo or RF catheters was necessary in 7.3% of patients. Major procedure related adverse events occurred in 20 patients (5.8%), the most frequent complication being PNI in 11 patients (3.2%), rest being 1 (0.3%) stroke, 2 (0.6%) asymptomatic PV stenosis, 3 (0.9%) hemoptysis and 3 (0.9%) pericardial effusions, one requiring pericardio-pH that affects the organelles, leading to irreversible lesions. At the same time microvascular injury occurs. As the thaw occurs, hyperemic vascular response and enlargement of the crystals extends further cellular damage. Following the thaw, infl ammation and hemorrhage ensue leading to more cellular destruction via edema and apoptosis. Lastly, the fi nal phase is comprised of tissue infi ltration by infl ammatory cells and eventual replacement fi brosis over weeks 43,92 . Several advantages of cryothermal energy have been recognized over RF energy including less patient discomfort, excellent contact by attachment of the catheter to the tissue during freeze, creation of well-demarcated and homogenous lesions, preservation of the tissue structural integrity and the lesions result in minimal endocardial surface disruption, being less thrombogenic 92 .
The original application of cryoablation was in the 1980s in surgical epicardial accessory pathway ablation 43 . Cryoablation for AF was introduced as adjunctive energy source for Cox-Maze procedures 16 . Afterwards, the endocardial focal cryo catheters were developed and used in AF ablations as "touch-up" lesion deliveries, usually for posterior antral regions of the pulmonary veins, when RF applications would result in signifi cant increase in esophageal temperature. However, the need for long application time of 3-4 min and freeze-thaw-freeze sequence, point-by point cryoablation was not a viable stand-alone solution for PV isolation. Thus one shot, cryothermal balloon ablation technology was developed, with fi rst system (CryoCath Technologies Inc., Kirkland, Canada) consisting of a non-defl ectable, over-the-wire 12-F two-lumen catheter with double inner-outer cooling balloons, with 23 mm or 28 mm diameter 93 . The refrigerant, liquid nitrous oxide, was delivered under pressure from the console into the inner balloon chamber with the 4 jets oriented towards the equatorial belt of the balloon. A liquid-to-gas phase change results in inner balloon cooling temperatures of ≤-80°C. The temperature during cryo application is monitored via a thermocouple located at the inner balloon. The initial study of feasibility on 57 patients took place in 2007 in Netherland and acute isolation using the cryoballoon (CB) only was achieved in 84% of the veins, the rest requiring touchup using focal cryo catheter 93 . At 3 months follow-up, using daily ECG recordings, 34 patients (60%) did not have any AF recurrence. There was a signifi cant reduction in mean AF burden at 3 months compared to baseline (24 ± 31% baseline to 5 ± 15% at 3 months p < 0.01). The only signifi cant com-and avoid collateral damages. A single 3 or 4 minutes CB application proved same effi cacy at one year as previously reported series, using 2 applications, with 71-82% freedom from AF at one year after single procedure [110][111][112] . Two randomized trials showed that shorter or single CB applications are as effective as 3-4 minutes freeze-thaw-freeze applictions 106,109 . The CIRCA-DOSE trial 106 randomized 346 patients with paroxysmal AF to CB application for 4 minutes, CB application for 2 minutes, each followed by an additional same duration application after PVI, and RF ablation using CF catheter. Freedom at one year from atrial tachyarrhythmia by continuous rhythm monitoring using a loop recorder was 52.2%, 51.7%, and 53.9% with 4-minutes CB application, 2-minutes CB application, and CF-RF, respectively (P=0.87). Freedom from symptomatic atrial tachyarrhythmia at one year was 78.2%, 73.3%, and 79.1% with 4-minutes CB application, 2-minutes CB application, and CF-RF, respectively (P=0.26). AF burden was reduced by a median of 99.9% (interquartile range, 65.3%-100.0%) with 4-minutes CB application, 98.4% (interquartile range, 56.2%-100.0%) with 2-minutes CB application, and 99.3% (interquartile range, 67.8%-100.0%) with CF-RF (P=0.36). Serious complications occurred in 4.6% of patients, with no difference between the treatment arms. There was one esophageal perforation in CF-RF group with pericardial abscess requiring surgical drainage, 3 (1.3%) PNI in the cryoballoon arm, all of which resolved, and 1 (0.9%) stroke occurred in the 4-minute CB arm. The AD-Balloon study 109 randomized 110 patients to either additional 3 minutes freeze cycle (AD group) after the freeze that led to PVI or not. Delayed enhancement MRI was performed in 62 patients (28 AD group and 34 non-AD group) to evaluate the lesions. At 1 year freedom from atrial tachyarrhythmias was 87.3% in the AD group and 89.1% in the non-AD group (log-rank test P=0.78). DE-MRI showed no signifi cant difference in the gaps on the PVI lines, 46% in the AD group versus 36% in the non-AD group (P=0.38). Complications occurred in 18 (16%), most of them being PNI in 8 (7%) patients, all resolved by last follow-up, 2 (2%) pericardial effusion/tamponade, 1 PV stenosis.
Although initially approved for ablation of paroxysmal AF, CB PVI has been an effective ablation strategy for persistent AF as demonstrated by non-randomized series 113,114 , and a meta-analysis 108 . More recently, the CB was approved in US for ablation of persistent AF ablation after CRYO4PERSISTENT AF trial 107 demonstrated to be a valid strategy. The single arm pro-centesis. At 36 months PNI persisted in 1 (0.3%) patient. Freedom from atrial arrhythmias recurrence was 79% at one year, 71% at 2 years and 64% at 3 years 97 .
Multiple studies and meta-analyses 98-100 showed similar results of CB when compared to standard RF ablation, with shorter procedure time, higher fl uoroscopy time and less non-AF atrial tachyarrhythmias 98 . The CB2 and CF RF catheters have improved the long term ≥12 months outcomes with freedom from atrial tachyarrhyhtmias of 78.1% and 78.2% respectively, compared to fi rst generation technology 57.9% with CB1 and 58.1% RF with non-CF catheters 98 . Serious complications has been shown to be similar between the two technologies 3.34% for CB2 and 2.94% for CF RF 99 , with less pericardial effusions and tamponade seen with CB, and PNI almost exclusively seen with CB 98-100 .
Phrenic nerve injury has been recognized to be one of the major Achile's heel of CB technology. This has been a known complication for other balloon based ablation technologies using different energies, given close proximity of right phrenic nerve and orifi ce of right sided pulmonary veins 101 and wider area of contact and displacement with balloon pressure forward to maintain occlusion. In one series of 100 patients undergoing focal RF ablation 102 , pace mapping of the phrenic nerve showed capture in 30% of the patients at the levels of anterior orifi ces of right veins and carina (85% at the carina level, 70% right superior vein and 30% at the right inferior vein). Reported incidence of PNI with point-by-point ablations is 0.17-0.48% 102 , however with CB technology could vary from 1-17% 98,100,101 . Stimulation of the phrenic nerve with pacing at the level of superior vena cava during has proven to be a valuable precaution during isolation of the right veins. A number of monitoring strategies of phrenic nerve capture have been employed, either direct tactile sensing of diaphragm contraction strength, direct visualization of diaphragm movement by intracardiac echocardiogram, or diaphragmatic compound motor action potentials (CMAP) recording using 2 surface electrodes at the level of the right diaphragmatic area 103,104 . Termination of the CB application with diminishing diaphragm contraction or more than 30% decrease in the CMAP signal amplitude showed to be effective in decreasing the incidence of PNI. Although most of recent series show a decrease in PNI incidence to 0-2% in [105][106][107][108] , there are still wide variations with some of the series reporting up to 9% PNI 109 .
Several protocols have evaluated the optimal CB application duration to maximize lesion effectiveness Dan Musat et al.

RADIOFREQUENCY HOT BALLOON
The SATAKE HotBalloon ablation system (Toray Industries, Inc., Tokyo, Japan) has outcomes data published from trials conducted mostly in Japan [116][117][118] . The system is composed of a balloon that can be infl ated up to 26 to 33 mm in diameter with 10 to 20 ml contrast medium and a radiofrequency generator that automatically controls the temperature of the balloon at a preset value (40°C to 70°C) and agitates the fl uid inside the balloon. The system uses radiofrequency current of 1.8 MHz delivered between the coil electrode inside the balloon and the 4 cutaneous electrode patches on the patient's back to induce capacitive-type heating in the balloon. The thermal energy conducted by the heated balloon, and not direct radiofrequency energy, is used for tissue ablation 116 . The acute success of pulmonary vein isolation using the balloon only ranged from 80-93%, with medium and long term success rates improving from 59% in the initial cohort 116 to 84-93% in subsequent series 117,118 . As the learning curve improved the initial high rates of pulmonary vein stenosis of 5.2% and phrenic nerve injury of 3.7% improved dramatically to none reported in subsequent series.

LASER ABLATION
Lasers use an optical fi ber with a radiating fi ber tip, in conjunction with a 980-nm wavelength diode, to produce high-energy coherent beams that absorbed by the water in the tissue result in dielectric heating 43 . Tissue destruction occurs by mechanical damage as well caused by shock waves. The visually guided laser balloon second-generation system (VGLB; Heart-Light; CardioFocus Inc, Marlborough, MA, USA) is comprised of a variable-diameter compliant balloon fi lled with deuterium oxide, a 2 mm endoscope allowing direct visualization of the PVs and diode delivering laser energy in 30° controllable arcs. The laser energy delivery is titratable, ranging from 5.5 W to 12 W for 20-30 seconds, depending on anterior or posterior wall delivery or presence of blood in the delivery fi eld. Direct visualization allows the operator to ensure complete vein occlusion to avoid delivery of energy to the blood, which could result in thrombus formation, or in the vein, to prevent stenosis. 43,89 The fi rst large randomized multicenter trial was The Heart-Light Study comparing safety and effi cacy of the second-generation VGLB to RF ablation (non-CF irrigated ablation catheter) 119 . The study randomized 353 patients with paroxysmal AF in one of the 2 arms. The acute PVI spective trial enrolled 101 patients with persistent AF and 100% AF burden of 7-180 days. At 12 months, 61% of patients were free of atrial tachyarrhythmias with symptomatic improvement in 76% of patients. Major adverse events occurred in 4% of the patients, 2 pseudoaneurysms, one transient ST elevation and one pericardial effusion not requiring intervention, and no PNI 107 .
The improved effi cacy and safety of the CB ablation as well as low success rates of antiarrhythmic medication led for consideration of CB PVI as the fi rst treatment strategy for patients with paroxysmal AF. Two recent randomized trials STOP-AF First (US only) with 203 patients and Cryo-FIRST (Europe, Australia and Latin America) with 220 patients randomized to CB PVI or medical treatment were reported as late breaking trials at European Congress of Cardiology, August 29 -September 1, 2020. The freedom from atrial tachyarrhythmias at 12 months was signifi cantly higher, 75% and 82% of patients, in CB arm compared to medically treated patients, 45% and 68%, respectively.
POLARx™ Cardiac Cryoablation System (Boston Scientifi c, Marlborough, MA, USA) is a new system using a compliant CB, with promising initial experience in 30 patients presented at Heart Rhythm Scientifi c Sessions May 8-11, 2019, and showed 100% acute PVI (33% single application), 100% EGM visualization in the veins with no serious adverse events at 30 days 115 . The Cryoballoon in the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial Fibrillation (FROZEN-AF) Investigational Device Exemption (IDE) study (Cli-nicalTrials.gov Identifi er: NCT04133168) currently started recruiting patients in June 2020 with an expected completion date in April 2022.
The cryoballoon technology has proven to be an excellent alternative strategy for treatment of paroxysmal and persistent AF with success rates similar to RF ablation, but improved procedural time and lower cardiac complications. The PNI still remains a concerning complication, however this is almost unanimously reversible.

ALTERNATIVE AND NEW ABLATION ENERGIES
In the race for the ideal energy for AF ablation, several other energies have been or are currently in evaluation including heat, LASER energy, high-intensity focused ultrasound (HIFU), liquid nitrogen, pulse fi eld electroporation.
blation catheter capable of adopting multiple shapes using different pre-formed stylets, with a distal portion used for mapping and proximal cryo application region (Figure 2). The refrigerant used by the system is liquid Nitrogen able of cooling temperatures to -196°C, with applications of 30-60 seconds for lesion creation. Esophageal protection is assured by continuous circulating saline at 36°C into a compliant intra-esophageal balloon. For the right veins ablation the right phrenic nerve is stimulated with pacing at the superior vena cava level. The initial in humans experience was reported at Heart Rhythm Scientifi c Sessions in 2018 124 , when the results of AF ablation in 32 patients were presented. All patients successful underwent PVI, some underwent additionally posterior wall isolation, cavo-tricuspid isthmus ablation and non-PV triggers ablation. At 6 months, 90% of patients were free of AF. Initial safety concerns included 2 PNI, that completely resolved; since introduction of the cryomapping, higher temperature for 30 seconds prior to going into full freeze, PNI was not seen in the last 19 patients. The system has received CE mark in Europe and currently iCLAS™ for Persistent Atrial Fibrillation IDE trial (ClinicalTrials.gov Identifi er: NCT04061603) is currently undergoing in several centers in US and Europe.
Adagio Medical recently also reported encouraging pre-clinical effectiveness of a Pulse Field Cryoablation (PFCA) catheter, combining ultra-low temperature cryo and electroporation.

PULSE FIELD ELECTROPORATION ABLATION
Irreversible electroporation (IRE) is a technology adapted from oncology, where is used for treatment of certain solid cancers 125 . Application of a high, pulsed electric fi eld (PEF) across the cell increases cell membrane permeability by creation of nano-pores, leading to loss of cell's homeostasis and death. The PEF is produced by high voltage direct current delivered between 2 or more electrodes 126 . The components for IRE delivery includes PEF generators, capable to provide high voltage electric fi elds of 250-3000 V and the catheters capable to deliver the PEF to the tissues through multiple channles 126,127 . Multiple preclinical studies were performed using different, custom developed, protocols typically for IRE a pulse duration of nano to microseconds, usually 100μs (the longer the pulse, the more tissue destruction), 10-90 pulses (the higher number of pulses, the higher the voltage), with a repetition frequency of 1-10 Hz (the higher frequen-was similar in both groups (99.7% VGLB group and 99.1% in the RF group). At 12 months, freedom from atrial arrhythmias, off antiarrhythmic therapy was similar in the VGLB and RF ablation group (61.1% vs 61.7%, P = 0.003 for noninferiority). As for safety in the VGLB arm a signifi cantly higher rate of diaphragmatic paralysis (3.5% vs 0.6%, P = 0.05) was encountered despite a protocol of phrenic pacing during ablation of the RSPV.
A meta-analysis including 17 studies that enrolled 1188 patients, 80% with paroxysmal AF, showed an acute PVI of 98.8% and a 12-month freedom from atrial arrhythmias of 72.9% (74.3% for paroxysmal AF). The most common procedural complication was PNI in 2.6% patients 120 .
The VGLB technology has several advantages including direct visualization of energy delivery, stable position with contiguous lesions, ability to titrate energy at different areas, however one of the concerns is the lack of a safety mechanism at high temperatures, so high energy application could result in crater formation and even tissue perforation 43 .

HIGH-INTENSITY FOCUSED ULTRASOUND ABLATION
High-intensity focused ultrasound (HIFU), with 20 kHz to 200 MHz range, produces water molecules oscillation in the tissues; the kinetic energy generated is converted to thermal energy that leads to tissue destruc-tion43. The HIFU system (ProRhythm, Ronkonkoma, NY,USA) is comprised of 2 non-compliant balloons: a distal one fl uid-fi lled (24 mm, 27 mm, and 32 mm) with an integrated 9-MHz ultrasound crystal, and a proximal second balloon fi lled with carbon dioxide. The catheter delivers non-titratable ultrasound energy in a focused ring at about 4 mm distal to the balloon's surface 89 . The initial studies 121,122 showed a relatively low acute PVI with a high incidence of irreversible phrenic nerve palsy and esophageal injury with a case of fatal atrioesophageal fi stula 89,123 . This led to discontinuation of human trials using HIFU catheter-based ablation. HIFU energy may still offer promise for surgical epicardial ablation, where transmural lesions are unhampered by epicardial fat 43 .

ULTRALOW TEMPERATURE CRYOABLATION
A novel intelligent Continuous Lesion Ablation System (iCLAS™, Adagio Medical, Laguna Hills, USA) now at its' third generation uses a 20 electrodes linear cryoa-Dan Musat et al. Atrial fi brillation ablation pite transmural lesion demonstration and application direct at the PV ostium 126 . The fi rst in-human study was reported by Reddy et al. 128 with 22 patients undergoing PV isolation, 15 endocardial and 7 epicardial approach. For endocardial ablation PV isolation was 100 % successful in all 57 PVs using a mean of 3.26±0.5 lesions. The epicardial approach was 86% successful (6 of 7 patients) using a mean of two lesions. There were no complications.
A new lattice-tip catheter (Sphere-9; Affera, Inc, Watertown, MA), capable to deliver RF and PFA pro-cy, the higher the heat generated) 126 . The attractiveness of this type of energy is the non-thermal mode of cell demise, ultra-rapid delivery (seconds) and most unique feature, tissue selectivity -tissues have specifi c characteristic threshold of PEF strength that leads to necrosis 43,127,128  was seen (<39°C). Esophagogastroduodenoscopy was performed in all the patients at 1.6±1.1 days and showed in PF/PFA group minor mucosal thermal injuries (5.6%) and no lesions in PFA group. Post-procedure brain MRIs were performed in 51of 76 (67%) patients at 1.2±0.6 days, revealing silent cerebral events in 8 of 51 (15.7%) patients, which was asymptomatic.
The fi eld of pulse fi eld ablation (PFA) is at the beginnings and despite excellent early results, long term data in effi cacy and safety are needed for its validation as a worthwhile ablation technology.
vided by a high-current RF and PF dual-generator, was studied in a multicenter, single arm trial that enrolled 76 patients 129 . For 40 patients RF was applied at the anterior wall and PFA (RF/PFA) to the posterior wall and in 36 patients only PFA was applied. Acute electrical PVI was achieved in 100% of the veins and conduction block was demonstrated in 99% of the lines performed. A thorough safety evaluation showed no device related complications. One vascular access injury required surgical correction. During ablation at the posterior wall, only low level esophageal heating

CONCLUSIONS
The fi eld of AF catheter ablation has evolved at an amazing pace over the past half century, PVI still remaining to date the cornerstone of catheter ablation procedure for both paroxysmal and persistent AF. Despite multiple advances in technologies, the success rate of the ablations is not comparable to the results of ablation for other supraventricular tachycardias. It is still unclear if the way to higher success is a better understanding the pathophysiology at various stages of AF or in developing better tools for PVI. The highest success is achieved in paroxysmal AF, with an effective and durable PVI, likely by addressing the AF PV triggers and neuromodulator inputs. However, once the disease process advances and AF becomes persistent, other factors, besides triggers, are likely involved in maintenance of AF, mainly the atrial substrate remodeling with dilation, scar formation and trigger regions other than PV. Several other ablation techniques, besides PVI, have been employed, including linear ablations, complex fractionated atrial electrograms (CFAE), ablation of non-PV triggers, rotor mapping and ablation with questionable successes. The STAR AF II randomized study 130 in patients with persistent AF showed that PVI alone is as good as PVI plus additional linear and/or CFAE ablations.
Currently several studies are recruiting or are in follow-up phase evaluating if additional techniques to the PVI as LAA ligation (aMAZE trial) 131 , posterior wall isolation (iCLAS trial), homogenization of left atrial scar regions detected by MRI (DECAAF II trial) improve the success of ablation for persistent or longstanding persistent AF. The results will be available in the near future, hopefully answering some of these unknowns.
The war on AF is not won yet, however many barricades have been conquered, understanding our pitfalls, towards a closer victory (Figure 2). Confl ict of interest: none declared.