Frozen Hearts: The Emerging Role of Cryoablation for Pulmonary Vein Isolation

Abstract

The cornerstone for the modern treatment of paroxysmal atrial fibrillation (AF) is pulmonary vein isolation, also called an AF ablation. Various ablation technologies exist to accomplish this goal with specific advantages. This chapter will focus on the unique attributes of cryoablation for pulmonary vein isolation. Specifically, we will summarize the trial data and outcomes of cryoablation in patients with paroxysmal and persistent AF from the initial FDA approval studies to novel uses beyond the pulmonary veins. Readers will have an appreciation of the unique characteristics differentiating cryoablation from radiofrequency (RF) catheter ablation and other techniques such as surgical MAZE. Clinical trial data show both noninferiority, and in some cases, superior outcomes of cryoablation to antiarrhythmic drug therapy and other ablation techniques.

1. Introduction

Atrial fibrillation (AF) is the most common sustained arrhythmia in the United States. Symptoms vary widely, and can include: palpitations, dizziness, chest discomfort, fatigue, shortness of breath, and stroke [1]. There are many factors that can increase one’s risk of developing AF which include: age, increased body mass index (BMI), hypertension (HTN), diabetes mellitus (DM), congestive heart failure (CHF), obstructive sleep apnea (OSA), and some genetic predispositions as well. In addition to these risk factors, certain lifestyle characteristics can also play a role in the development or perpetuation of AF. These factors include smoking, alcohol, and psychosocial stress [2].

For patients with AF, the two principal goals of long-term therapy are to improve quality of life (e.g., symptom control) and to prevent associated morbidity and mortality. Rate and rhythm control strategies both can improve symptoms, but interestingly, neither has been conclusively shown to improve survival compared to the other. For those patients in whom a rhythm control strategy is chosen, catheter ablation or antiarrhythmic drugs are the two principal therapeutic options. This chapter will review the efficacy and safety of these two options for rhythm control and provides rationale for choosing one versus the other [3].

The incidence and prevalence of AF has been increasing globally. Data from the Framingham Heart Study demonstrated that the prevalence of AF increased 3-fold over the past 50 years [4]. The prevalence of AF doubles with every decade of life and reaches close to 9% in the ninth decade. In 2019, AF was mentioned on over 180,000 death certificates and was the underlying cause of death in approximately 15% of those deaths. According to the CDC, it is estimated that more than 12.1 million individuals in the United States will have AF in 2030. The worldwide prevalence of AF was approximately 46.3 million individuals in 2016 [5]. In Europe, the prevalence of AF in 2010 was 9 million among people older than 55 years and is expected to reach around 14 million by 2060 [6].

Clinically, AF can be classified by the duration of episodes and responsiveness to therapies as follows:

1. Paroxysmal AF (PAF) is characterized as self-limited episodes of AF typically separated widely, with no episode lasting greater than seven days.

2. Persistent AF, which is characterized by AF that is present for more than seven days or with a need for intervention to resume sinus rhythm (chemical or electrical cardioversion).

3. Permanent AF, where cardioversion is either not effective, or sinus rhythm reverts back to AF immediately.

AF is a complex process that results in rapid and disorganized atrial activation. Understanding the mechanisms of AF helps to understand the rationale behind the therapeutic interventions. The triggers for AF episodes most commonly are premature atrial contractions (PAC) which originate from within the pulmonary veins (PVs). Increased time in AF leads to structural changes throughout the atria such as scarring and fibrosis. These changes decrease the likelihood of spontaneous conversion to normal sinus rhythm (NSR) in patients with persistent or permanent AF [2, 7, 8].

The goal in circumferential pulmonary vein isolation (PVI) is to electrically separate the left atrium from the source of the PAC foci within the pulmonary veins. Circumferential pulmonary vein ablation has several putative mechanisms of action and is the mainstay for ablative treatments for AF. Other mechanisms by which circumferential ablation is believed to be effective are by concomitant ablation of the autonomic ganglia, which are found near the pulmonary vein ostia. Circumferential ablation is typically recommended for patients with PAF; however, it can also be beneficial for patients with persistent AF alone or in combination with additional ablation sites.

2. Catheter ablation vs. antiarrhythmic drugs

For patients with either paroxysmal or persistent AF who desire sinus rhythm, catheter ablation or long-term antiarrhythmic drug therapy are the two available approaches. There are defined risks and benefits to the different approaches. This section will review the studies that have directly compared them. It is important to note that this section is not intended to address management of patients who have failed rhythm control with two or more antiarrhythmic drugs or those who have already received catheter ablation. Antiarrhythmic drug therapy failure is defined as a trial of a drug that results in reduction in AF burden that is not satisfactory to the patient, or results in side effects that are intolerable to the patient, proarrhythmic, or result in organ toxicity [9, 10]. Prior to the 2020 ACC / AHA / HRS guidelines, catheter ablation (CA) was generally recommended as second line therapy after failure of AADs. However, mounting evidence suggested that CA is superior to AAD for the control of symptoms and maintenance of NSR. CA is now accepted as a first-line therapy for symptomatic patients after a comprehensive discussion of the benefits and risks of both approaches [3, 11].

Typically, evaluation of the various AF treatment strategies includes reference to the time free of AF in the year following treatment initiation. This is commonly referred to as the 1 year AF free survival. The 1 year data commonly excludes the 90-day blanking period following treatment to allow for post-ablation healing. An AF free survival of 100% would mean no patients had AF recurrences, and 0% 1 year AF free survival would mean all patients studied had recurrence within a year. Three early meta-analyses of studies comparing catheter ablation and antiarrhythmic drug therapy found that AF free survival was higher in the ablation treatment arm as compared to the AAD treatment arm [12, 13]. In the EARLY-AF trial, 303 patients were assigned to either AAD group (n = 149) or cryoablation group (n = 154). All the patients in both groups received an implantable cardiac monitoring device to assess AF recurrences and the follow-up period was 12 months. The first documented atrial tachyarrhythmia included for analysis had to occur between 91 and 365 days after CA or AAD initiation. The AF free survival was 89% of patients who underwent CA and 74% of the patients who were started on AAD (hazard ratio, 0.39; 95% CI, 0.22 to 0.68) [14]. Another study demonstrated similar results, which reported an 1-year AF free survival of 58% of patients undergoing CA and 32% of patients assigned to AAD therapy (hazard ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66; P < 0.001) [15]. In another trial that included 203 patients, 104 underwent CA and 99 received AAD therapy. In the ablation group, the procedure had initial success in 97% of the patients. The 1 year AF free survival was 74.6% (95% confidence interval, 65.0 to 82.0) in the ablation group and 45.0% (95% CI, 34.6 to 54.7) in the drug-therapy group (P < 0.001) [16, 17].

Important complications of AF ablations include cardiac tamponade (about 1%), pulmonary vein stenosis (<1%), phrenic nerve paralysis (~ 3%with cryoballoon), and rare instances of stroke and atrioesophageal fistula. Of the 303 patients in EARLY-AF, serious adverse events occurred in 5 patients in the CA group (3.2%) and in 6 patients (4%) of patients in the AAD group. Commonly prescribed drugs to maintain sinus rhythm are amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone. These medications range in efficacy from 40 to 60% 1 year AF free survival in meta-analyses. Important AAD medication side effects include proarrhythmia, bradyarrhythmia, organ toxicity, and death [17]. AAD selection is influenced by the patient’s comorbid conditions such as CHF, CAD, structural heart disease, kidney function, and liver function. Guidelines exist to help in the selection of the appropriate agents with these comorbid conditions in mind to minimize potential drug toxicities and side effects. However, the guideline adherence when prescribing these medications is poor [18]. Importantly, all patients need to be informed of the possibility of recurrence of AF and adverse events with both catheter and medication-based rhythm control strategies.

Evaluating RF ablation versus AAD, the ThermoCool AF study randomly assigned 167 symptomatic patients with PAF who failed at least one AAD and who experienced at least three episodes of paroxysmal AF within the six months prior to randomization to either catheter ablation (with RF) or AAD therapy. Patients with significant left ventricular dysfunction, persistent AF, and advanced heart failure were excluded. Catheter ablation included PVI with confirmation of entrance block, and AAD therapy included flecainide (36 percent), propafenone (41 percent), dofetilide, sotalol, or quinidine at the investigator’s discretion. After nine months, there were significantly fewer patients with documented symptomatic paroxysmal AF in the catheter ablation group (84 versus 34 percent AF free survival; hazard ratio 0.30, 95% CI 0.19–0.47). In addition, major treatment-related adverse events occurred more often with AAD therapy (9 versus 5 percent) at 30 days. Mean quality-of-life scores improved significantly with catheter ablation compared to AAD therapy [19].

A similar trial to ThermoCool AF was conducted for the cryoballoon catheter. The STOP AF trial is an important trial that specifically studied the use of AADs versus CA in patients with PAF. There were a total of 245 patients studied, all with either a diagnosis of PAF or persistent AF. All the patients included in the study had a history of previous AAD failure. In the AAD group, patients were randomly assigned to flecainide, propafenone, or sotalol. A “blanking period” was used in this study, which essentially allowed for medical optimization of any AAD or necessary re-ablation in the CA group. Treatment success was defined as the freedom from any detectable AF after the blanking period. The patients in both the experimental groups were followed for twelve months following intervention. Among those in the AAD group, 78% with PAF and 22% with persistent AF experienced failure of at least one AAD. On the other hand, 98.2% of patients in the CA group achieved acute isolation in three or more of the PVs, and 97.6% in all four PVs. A 1-year AF-free survival was found in 69.9% of CA patients, and 7.3% of patients in the AAD group. Among those patients who underwent CA, symptoms were significantly improved at the twelve-month mark as well [20].

The Catheter Ablation vs. Antiarrhythmic Drug Therapy in Atrial Fibrillation (CABANA) trial was a more recent large clinical trial looking at catheter ablation versus AAD in patients with AF. This study also evaluated patients with either paroxysmal (43%) or persistent AF (57%) and randomly assigned each patient to either AAD or CA therapy. Patients were excluded from the study if they had any prior catheter ablation procedure or failure of two or more antiarrhythmic drugs. It is important to note that in this study, of the patients who received AAD drug therapy, 27.5% crossed over to the ablation group. The primary endpoint of this study was death, disabling stroke, serious bleeding or cardiac arrest, which occurred in 8.0 and 9.2% in the AAD and CA groups, respectively during the 4 year follow up period. There was no significant difference in all-cause mortality (5.2% vs. 6.1%) among both respective groups. The trial showed that the combined end point of death or cardiovascular hospitalization occurred less often among those who underwent CA as it did for recurrence of AF. The quality of life scores for each group showed significant improvement. However, those in the CA group reported significantly greater improvement than the drug therapy group at twelve months with scores of 86.4 and 80.9 points, respectively, with a baseline reference value of 63 points [21].

To further assess the efficacy and safety of CA as compared to AADs as first line treatment for PAF, a meta-analysis was conducted of six studies that compared CA with AAD. Among studies in the meta-analysis, a total of 1200 patients were included. Catheter ablation was associated with lower rates of recurrent atrial arrhythmias consistently. The risks of serious adverse events, including stroke, cardiac tamponade, and death were also evaluated. It was demonstrated that lower rates of symptomatic atrial arrhythmias, lower healthcare resource utilization, and lower rates of crossover to alternative treatment were all associated with first line CA strategy. However, this particular meta-analysis did have limitations which included a moderate degree of heterogeneity among the included studies most notably the RAAFT 2 trial [22].

The CASTLE AF trial demonstrated improved outcomes with upfront ablation among patients with chronic systolic congestive heart failure who are otherwise receiving appropriate treatment [21]. CASTLE AF used implantable cardioverter defibrillators equipped with AF monitoring capabilities to study AF recurrences in patients after randomization to initial catheter ablation or AAD therapy. Patients were excluded if they had a prior history of daily use of class I or class III antiarrhythmic drugs. The primary endpoint was considered to be death or hospitalization for worsening heart failure, and this was demonstrated in significantly fewer patients in the CA group in comparison to the AAD group. After a 60 month follow up period, 63.1% of the patients in the CA group and 21.7% of patients in the AAD group remained in sinus rhythm. In other words, the CA patients had a significantly lower recurrence of AF than those in the AAD group. In terms of mortality, fewer patients in the ablation group (28.5%) in comparison to the AAD group (44.6%) experienced the primary endpoint of death from any cause [10, 23].

In summary, CA is useful for symptomatic paroxysmal AF as a first line therapy when a rhythm control strategy is desired. Catheter ablation for AF is safe and effective with similar or improved outcomes as compared to AADs for long term AF management with fewer long-term complications. Upfront catheter ablation as noted in the CASTLE-AF trial is associated with reductions in all-cause mortality in patients with CHF. A discussion with patients regarding these risks and benefits should guide decisions on which strategy to utilize in the maintenance of normal sinus rhythm (NSR).

3. Cryoablation vs. radiofrequency

Catheter ablation is now a well-established interventional approach for treating symptomatic, drug refractory PAF with class I level A guidelines recommendation. A 2017 randomized comparison between cryoablation and RFA showed similar success rates, as did a meta-analysis of observational studies. Historically, catheter ablation using either cryoablation or radiofrequency ablation demonstrated 60–80% 1 year AF free survival.

Cryoablation for arrhythmias has been used for cardiac surgery for decades. However, transvenous catheter cryoablation for arrhythmias have been used only since the 2000s. The main purpose of cryoballoon ablation (CBA) is to isolate pulmonary veins (PVs) with single energy application for encircling lesions at the antral level of the PVs. Conventional radiofrequency catheter ablation (RF) was characterized by point-by-point ablation to create a line which requires multiple energy applications to accomplish PVI [24].

The procedure of cryoablation is performed in the cardiac catheterization / electrophysiology laboratory. Access is typically obtained through the right femoral vein. Additional access is often required from the left femoral vein and/or the axillary or internal jugular vein depending on the operator’s preference. The ablation technique for cryoballoon ablation is similar to that of radiofrequency ablation in that a septal puncture is used to access the left atrium with the goal of PVI. In the case of cryoablation, only a single transseptal puncture is required though at a lower anterior septal location. This location is recommended to allow more space for the cryoballoon to move and provide better support to the PVs, especially the right inferior PV [10].

With the assistance of fluoroscopy, and 3D electroanatomical mapping technologies including intracardiac echocardiography; transseptal puncture is performed to gain access to the left atrium. The ablation can be made in any sequence, but it is commonly started with the left superior pulmonary vein then left inferior pulmonary vein followed by the right inferior pulmonary vein and finally the right superior pulmonary vein [1]. Esophageal temperature monitoring is frequently performed to avoid potentially dangerous cooling of the esophagus during adjacent LA cryoablation. Similarly, the right phrenic nerve is paced during right-sided pulmonary vein applications to avoid phrenic nerve damage. After ablation is completed, a mapping catheter is placed into each pulmonary vein to check for proper electrical isolation. A vein is considered acutely isolated if it demonstrates entrance and exit electrical block [25].

Radiofrequency is completed using a current which is applied in a point-by-point method. The resistive current allows for the tissue to be heated, and this results in cellular necrosis. Alternatively, the use of cryothermal energy, which is applied with a balloon, differs from the former as it allows for cellular necrosis via freezing [24]. Cryoballoon technology is increasingly used for treating AF. Although commonly there are 2 right-sided and 2 left-sided pulmonary veins, there are frequently noted anatomical variants. Cryoballoon ablation for PAF was associated with similar clinical outcomes as radiofrequency independently of the anatomical pulmonary vein distribution pattern. The presence of a left common ostium or right middle vein was found to have similar clinical outcomes after cryoablation when compared with a control group treated by standard radiofrequency ablation. Pulmonary vein anatomical variants should not influence the choice of cryoballoon ablation [26].

There are many studies that compare the efficacy of cryoballoon ablation to radiofrequency, and a few of those trials have been outlined below. However, it is important to note that many of these studies involve relatively small sample sizes which are accompanied by a number of confounding variables. Systematic literature reviews and meta-analysis evaluating efficacy of cryoablation versus radiofrequency ablation for treating paroxysmal AF are helpful to make comparisons in this light [10, 26]. In a meta-analysis by Yi-He Chen et al., of 273 scholarly articles containing comparison between radiofrequency ablation and cryoablation of PAF. There were a total of 7195 participants studied, approximately one third (2863) underwent cryoablation and two thirds (4332) underwent RF ablation. The mean age of the patients was 59.9 years old, with a history of PAF ranging from 2.1 to 5.2 years. The study types included were retrospective cohort and prospective cohort with one study being ambi-directional. Cryoablation of the pulmonary vein was performed with a second generation cryoballoon within the majority of the studies. The mean follow-up duration ranged from 12 to 18 months. There is no evidence of significant differences for patient baseline demographic characteristics between the CA and RF ablation groups [26]. The overall freedom from AF/atrial tachycardia relapse was 65.6% with CA and 60.1% with RF ablation in follow-up of 12 months. The pooled estimate of relative risk ratio indicated that PVI was achieved by CA and RF ablation, which lead to comparable long-term AF/atrial tachycardia free survival during follow-up. Relative risk was 1.05 with a 95% confidence interval of 0.98–1.13, P = 0.159. There were no statistically significant interactions between the pooled RR and prespecified covariants. Data on procedure related adverse events were available for meta-analysis in 15 studies. Events occurred in 223 of 2759 patients (8.08%) with cryoablation and 333 of 4130 patients (8.06%) with RF ablation. No significant difference was found between these 2 approaches for ablation procedure-related adverse events [26].

The FIRE AND ICE trial, the largest prospective multicenter comparison between the two techniques, demonstrated that the cryoballoon is noninferior to radiofrequency ablation (RFA) in efficacy. The primary efficacy endpoint was defined as the first documented clinical failure (recurrence of AF, episodes of atrial flutter, start of antiarrhythmic agent, or repeat ablation). The study also demonstrated no significant difference with regards to overall safety. There were no reports of deaths, esophageal fistulas, or pulmonary vein stenosis. With regards to concerns about phrenic nerve injury the study showed only 1 in 300 patients developed permanent phrenic nerve injury at 12 months.

There was no significant difference in fluoroscopy time between the 2 approaches but overall procedure time in CBA was significantly less. This is due to the fact that CBA is a 1-shot catheter rather than the point-by-point approach in RF ablation to achieve pulmonary vein isolation. The point-by-point RF mapping has a more complex learning curve as it requires great skill and is more technical than CBA. This is what is making CBA one of the most widely used catheter techniques.

RF ablation results in irreversible tissue damage via heating. In CA, the freezing process involves ice crystal formation. This allows for an osmotic gradient to develop, which subsequently leads to acute cell death. This mechanism of cell death involves cellular swelling and disruption of the membrane integrity by means of further osmotic insult. The histopathological features of CA may be responsible for relatively demarcated lesions with minimal tissue architectural disruption. This has been found to contribute to a lower risk of thrombus formation and perforation. In addition, cryoballoon CA has also demonstrated catheter adhesion to pulmonary vein (through freezing) and thus the prevention of dislodgement [27, 28].

The long-term freedom from AF at 12-month follow-up and overall postoperative complication rates is also important to evaluate. One meta-analysis reviewed 247 articles, with a total of 8 studies encompassing 1548 patients who underwent either cryoballoon or radiofrequency ablation. This is representative of data from Europe between 2012 and 2015. Overall, it was found there is no significant difference between the freedom from AF after 12 months between both groups cryoballoon and radiofrequency ablation. Secondary outcomes during the ablation at the fluoroscopy time the ablation time failed to reach significance as well. Cryoablation had a significantly greater odds of postop phrenic nerve injury after 12 months [29].

A novel way of comparing the effectiveness of cryoballoon ablation and radiofrequency ablation was demonstrated by Trippoli et al. with a pooling method referred to as the Shiny method. The Shiny method is based on an artificial intelligence that reconstructs individual patient data. Using the Shiny method is unique because it accounts for follow-up length. This method was used for reevaluation of a meta-analysis. The advantage to using this method in re-analysis is because researchers are able to evaluate the probability of the end-point in the long term. The primary endpoint was time to recurrence of AF in patients who were enrolled in randomized studies comparing CA to AAD, RF to AAD, and CA to RF. Overall, CA showed a statistically significant higher effectiveness than AAD therapy. In the comparison of AAD to RF, no statistically significant difference was observed. This suggests that the results generated by the Shiny method from previously published meta-analysis were able to account for the effects of randomizations performed in the trials, along with accounting for length of follow up in the individual trials [30].

Atrial esophageal fistula is a well described complication of RF ablation where an abnormal potentially life-threatening connection forms between the esophagus and right atrium by a mis-match repair mechanism. It is hypothesized that this occurs due to inflammation caused by energy delivery to the posterior wall of the left atrium adjacent to the esophagus. Although initially believed to be a unique complication related to RF ablation, cryoablation has also been associated with this potentially fatal complication though far less frequently. A study by Ripley et al. dives further into the adverse effect of esophageal lesions after catheter ablation with cryoballoon and RF ablation and the implication for atrial esophageal fistula formation. The effects of direct application of RF and cryoablation on the cervical esophagus were evaluated in 16 calves. Cryoablation was performed with a 6.5 mm catheter probe using a single 5-minute freeze at less than −80°C. RF ablation was delivered with an 8 mm catheter electrode at 50 W and 50°C for 45 to 60 seconds. Histopathological assessments were performed at 1, 4, 7, and 14 days after the completion of both ablation procedures. This article evaluated the direct application of cryoablation and RF ablation in the left atrium and its effects on the esophagus. Although, on day 14 lesions in both groups on the esophagus were comparable in size, there was histological evidence of partial to full wall esophageal lesion ulceration associated with 0 of 44 cryoablation lesions and in 9 of the 41 lesions with RF ablation (P equals 0.0025). In other words, Cryoablation was associated with a significantly lower risk of esophageal ulceration [30].

4. Cryoballoon evolution

RF ablation catheters have made advancements over the years but they still rely on a “point-by-point” technique to achieve PVI which can be challenging and time-consuming. This is due to the fact that RF ablation utilizes focal catheters as opposed to a balloon system that can produce circumferential continuous lesions resulting in shorter TTI and durable PVI.

The Arctic Front™ is the first cryoballoon catheter system introduced in the United States, and was used in the North American STOP AF trial. The study found that the first generation CB was a safe and effective alternative to antiarrhythmic therapy. Procedure times were sped up to about one third when compared to spot ablation techniques.

Evolution of CB from first to the second-generation included the addition of 4 jets, increased refrigerant flow, and moving the cooling zone more distally. These changes made the CB more efficacious. The second generation CB was used in the FIRE and ICE trial that demonstrated Cryoablation to be noninferior to RF ablation.

The latest technological advances in the family of CB include improved visualization of TTI and maneuverability of the catheter. Further modifications are inevitable and will surely provide even safer and more efficient catheters [31, 32].

5. Stereotaxis

Guiding the catheter to the intended sites and maintaining adequate contact is a critical part of a successful procedure. The ability to see left atrium anatomy reduces complications and ensures that lesions are made at intended target sites. Fluoroscopy was the main imaging technique used by electrophysiologists to target the ablation site however it had several drawbacks including 2-dimensional (2-D) representation, inability to visualize soft tissue, and a long learning curve. Other modalities to facilitate accessing the left atrium anatomy include intracardiac echocardiogram, computed tomography (CT) and magnetic resonance imaging (MRI).

Remote magnetic navigation (Stereotaxis) entered clinical use for electrophysiology interventional procedures several years ago. Using stereotaxis may help reduce the risk of complications and increase the patient’s safety. The system creates a weak magnetic field around the patient that can be manipulated by an integrated computer and three-dimensional mapping system to drive flexible catheters within the heart with extreme precision.

Over the past 10 years, AF ablation has become the predominant indication in centers of excellence, possibly representing up to 60% of interventions. The main difficulties during these procedures are the duration, which may exceed 4 hours, and the length of time that both the operator and patient are exposed to radiation. The advantages of the technique were underlined by different authors, who highlighted that there was no risk of perforation, the catheter had excellent stability, and it was possible to navigate in complex anatomies, as has been described in patients with congenital heart defects. Although AF ablation was noticeably effective in 80% of cases, with a mean of 1.3–1.7 procedures per patient, the rate of major complications reported was 4.5% of cases, including 1% vascular accidents and 1.3% tamponade [33].

Several clinical trials have now been undertaken to evaluate RMNS in AF. The initial phase evaluated the feasibility of RMNS in 40 AF patients who required treatment by RFA. The authors demonstrated the feasibility and very good efficacy of the robotic technique. Application time was significantly reduced compared with the control group, although the trial was a case-control study.9. The operator highlighted the extreme stability of the magnetic catheter, which was especially useful for approaching the right veins. In the study, success was achieved in 38 of the 40 patients tested (95% of cases) [34].

6. Other ablation strategies

Beyond minimally invasive strategies, there are surgical ablation techniques most well known of which is the COX-MAZE (CM) procedure. Surgical approaches to AF ablation vary in the technique and level of published research investigating outcomes. With changes in the goals of the procedure the CM has been revised multiple times with each interaction being assigned a roman numeral. The CM IV procedure had significantly shorter mean aortic cross-clamp time for a lone CM from 93 ± 34 min for the CM III to 47 ± 26 min for the CM IV (P < 0.001). A propensity analysis performed by Lall et al. showed no significant difference in freedom from AF at 3, 6 and 12 months postoperatively between appropriately matched patients undergoing either the CM III or the CM IV [34]. A report of over 2 decades by Weimar et al. demonstrated both the CM III and CM IV showed no difference in freedom from AF and a significantly decreased major complication rate. This was despite the fact that the recent cohort had more patients with long-standing persistent AF and much more intensive follow-up with the majority of patients having at least 24-h Holter monitoring [34].

A more recent CM IV study reviewed 576 consecutive patients who underwent the CM IV between January 2002 and September 2014. Most patients were followed up with prolonged Holter monitoring. Twelve-month freedom from AF was 93%, with 85% of patients free from all AADs, while 5-year freedom from AF was 78%, with 66% of patients also free from all AADs. When comparing patients with PAF to patients with persistent AF, freedom from AF on and off AADs was not significantly different at any time point [35].

The CM has been successful in reducing the incidence of stroke. In a report by Pet et al., 13% of the patients had experienced a preoperative neurological event out of the 433 studied. However, there were only 6 postoperative neurological events during long-term follow-up in this cohort (mean 6.6 ± 5.0 years). The long-term stroke rate after the CM has been 0.2% per year, despite the fact that the great majority of patients had discontinued AADs [36].

Other cardiac diseases are often seen along with AF, and the CM is commonly used as an associated procedure. In patients who underwent mitral valve surgery, studies have demonstrated similar arrhythmia recurrence rates in patients with lone AF who have undergone stand-alone surgical ablation compared to those with AF and mitral regurgitation who underwent concomitant mitral procedures. Specifically, freedom from AF and AADs at 12 and 24 months were nearly the same between the 2 groups (73% vs. 76% at 12 months, 77% vs. 78% at 24 months) [37]. Another prospective, randomized control trial which was performed at the Cardiothoracic Surgical Trials Network (CTSN) compared patients with persistent or long -standing AF with patients who had mitral valve disease that required surgical intervention. The experimental groups either underwent CA or no ablation. The results demonstrated that the patients that remained free from AF at both 6 and 12 months belonged to that of the CA group with P < 0.001. It is important to note that those patients that underwent CA did not significantly affect morbidity or mortality.

A comparison between patients undergoing stand-alone CM-IV to those undergoing CA with aortic valve replacement was just as effective as stone-alone CM IV in the treatment of AF among all ages and all comorbidities [38]. Outcomes of patients with AF that were planning on having left or biatrial CM IV and coronary artery bypass grafting (CABG) in the years of 2002 to 2015 demonstrated significantly low operative mortality rates. Freedom from AF at 1 year in the CM-IV group was upwards of 98% with 88% free of AADs at the 5 year follow up period [35, 36, 37, 38].

Minimally invasive right minithoracotomy (RMT) is an alternate approach to standard surgical sternotomy approach. RMT has been associated with reduced operative morbidity and decreased intensive care unit stays. Major surgical complications were also found to be significantly lower in the RMT groups in composition to standard surgical approach [39].

In the last 3 decades, the development of ablation technologies has positively impacted the field of AF surgery and patient outcomes. Minimally invasive technologies have decreased the need for CABG procedure time, and with minimally invasive technologies come improved morbidity and mortality for patients. The number of patients undergoing surgical ablation procedures has been vastly increasing in the past 2–3 decades; however, there are still a significant number of patients with AF that are undergoing other cardiac interventions without treatment for their AF. With increased research and knowledge, increased education can encourage more aggressive treatment of AF in these patients. As continued learning of AF and the mechanisms of which it can develop evolves, improved diagnostic technologies can be implemented to a larger volume of patients [40].

7. Alternate uses/future directions

Based on this biophysical characteristic of preserving the tissue architecture, cryoablation was preferred to reduce the risk of causing destruction to the normal structure during specific arrhythmias such as atrioventricular nodal reentrant tachycardia or tachycardia originating near the His bundle region. These characteristics explain the lower risk of cardiac perforation or thrombogenicity compared to RFA. Cryothermal energy is produced during refrigerants injected through a fine tube. The refrigerant vaporizes at the tip of a cryoablation catheter and can freeze the adjacent tissue. While freezing, the catheter tip adheres to the affected tissue, which enables the application of stable energy [41].

A high cooling power and culture with culture cryoablation also called Adagio combination of newly exploited cryogenically interchangeable stylette needles. Flexible continuous leak and creation of other tachyarrhythmia by optimizing her catheter shape. Patients who underwent AF ablation enrolled in this procedure in the assessment of the procedural data that was focused on safety comprising first-pass isolation and defined as a successful PVI after initial application. The studies follow sequential PV isolation using the Novell UL TC catheters to visit without compromising safety the first-pass isolation was accomplished about half of the PVs.

8. Conclusions

The cornerstone for the modern treatment of paroxysmal atrial fibrillation (AF) is pulmonary vein isolation, also called an AF ablation. Various ablation technologies exist to accomplish this goal with specific advantages. Upfront ablation strategies have been shown superior to AAD in certain patient populations. One unique ablation technology for pulmonary vein isolation is Cryoablation. Clinical trial data shows both non-inferiority, and in some cases, superior outcomes of cryoablation to antiarrhythmic drug therapy and other ablation techniques. Cryoablation has been shown to be safe, and effective in various common anatomic configurations. An evolving technology, newer generation cryoballoons offer improved efficacy and continued safety.

Acknowledgments

We would like to acknowledge and thank Community Medical Center for the support of the program and in specific, Jagan Vanjarapu MD and Nelson Okoh MD.

Thank you/notes

Thank you to our supportive families without which none of this would exist.

Appendices and nomenclature

AF

Atrial Fibrillation

BMI

Body Mass Index

HTN

Hypertension

DM

Diabetes Mellitus

HF

Heart Failure

OSA

Obstructive Sleep Apnea

PAF

Paroxysmal Atrial Fibrillation

AAD

Anti Arrhythmic drugs

CA

Cryoablation

RF

Radiofrequency

PNP

Phrenic Nerve Palsy

PVI

Pulmonary Vein Isolation

RMNS

Remote Magnetic Navigation System

AV

atrioventricular

RFA

Radio Frequency Ablation

CM

Cryo Generation

CABG

Coronary Artery Bypass Grafting

RMT

Minimally invasive right minithoracotomy

CB-1

First generation cryoballoon

CB-2

Second generation cryoballoon

cryo-AF

Cryoablation of AF