Effect of cryothermic and radiofrequency Cox‐Maze IV ablation on atrial size and function assessed by 2D and 3D echocardiography, a randomized trial. To freeze or to burn

Atrial linear scars in Cox‐Maze IV procedures are achieved using Cryothermy (Cryo) or radiofrequency (RF) techniques. The subsequent postoperative left atrial (LA) reverse remodelling is unclear. We used 2‐ and 3‐dimensional echocardiography (2‐3DE) to compare the impact of Cryo and RF procedures on LA size and function 1 year after Cox‐maze IV ablation concomitant with Mitral valve (MV) surgery.

Atrial fibrillation (AF), the most encountered arrhythmia in clinical practice, carries a significantly increased risk of thromboembolic events and heart failure, which are an important cause of comorbidity and mortality worldwide.It occurs with a high prevalence in patients with mitral regurgitation (MR), presenting in over half of those referred for mitral surgery (McCarthy et al., 2020).The original surgical ablation technique is generically referred to as cut-and-sew Cox-maze III treatment.The Coxmaze IV procedure is a simplified alternative method of creating atrial lesions using different energy sources, which can be added to mitral surgery to restore sinus rhythm (SR) in cases of AF.The maze procedure is now a Class I recommendation for selected patients, as it has reduced AF recurrence in randomized controlled trials (Calkins et al., 2018) and decreased early and late mortality in risk-adjusted cohort studies (Badhwar et al., 2017).Two available techniques to achieve linear scars in the atria are cryothermy (Cryo) (freezing the myocardium) and radiofrequency (RF) (heating the myocardium).Several studies demonstrate that the efficacy of SR restoration is quite similar with the two energy sources; however, when studying the impact of ablation on the myocardium, Cryo procedures are associated with broader lesion width and a higher degree of myocardial injury in both open surgery and catheter ablation patients (Boano et al., 2020;Casella et al., 2014;Kurose et al., 2018).There is a growing interest in the assessment of left atrial (LA) remodelling following mitral valve surgery and after maze procedures, as LA size and function have an impact on long-term clinical outcomes (Kim et al., 2010;Park et al., 2014).Two-dimensional echocardiography (2DE) and three-dimensional echocardiography (3DE) are the most used noninvasive imaging techniques for assessing atrial size and function.Compared to 2DE, current 3DE allows an accurate volume definition, providing volumes during the three atrial phases: reservoir (filling), conduit (passive emptying), and booster pump phase (active emptying) (Mor-Avi et al., 2012).The 3DE technique shows less interobserver variability and is ideal for serial measurements (Badano et al., 2016).
In the present study, we aimed to use 3DE in addition to LA strain by speckle tracking echocardiography, to evaluate the impact of the two different energy sources, Cryo and RF, on LA size and function in patients with restored SR 1 year after the ablative procedure concomitant with mitral valve surgery.

| Study population
We performed a prospective, parallel, single-centre study with three groups, of which two were randomized.We consecutively screened 105 patients with preoperative AF scheduled for mitral valve surgery between September 2013 and July 2018 at Linkoping University Hospital (Figure 1).In the context of a multidisciplinary conference, an arrhythmia group, comprising cardiologists and cardiac surgeons, discussed the indications for whether to add surgical ablation.A total of 72 patients were considered eligible for mitral surgery and maze IV treatment and were randomly assigned, at a 1:1 ratio in blocks of 10, to undergo concomitant AF ablation with either a Cryo device (Cryo group, n = 35) or RF device (RF group, n = 37).The remaining patients were enroled in the protocol but did not undergo concomitant ablation and were thus not randomized (NoMaze group, n = 33).These patients had a low AF burden (one to two verified AF episodes), had severe comorbidities or the guidelines (Dunning et al., 2013) indicated that additional aortic crossclamp time (and the associated prolonged ischaemia) was too hazardous.
In addition to mitral valve surgery, some patients underwent aortic surgery (10 patients; 9%), tricuspid surgery (76 patients; 72%), and/or coronary revascularization (25 patients; 24%).All patients underwent transthoracic echocardiography within 24 h before the procedure.One year after surgery, the patients were offered an echocardiogram and a medical survey.This study was approved by the Regional Ethical Review Board (2012/371-31).Patients were enroled after providing written informed consent the day before surgery.

| Ablation methods
Cryoablation was performed using the argon-powered Cardioblate ® CryoFlex™ Surgical Ablation Probe (Medtronic Inc.).The probe was applied for 120 s, and the temperature fell rapidly (Joule-Thompson effect) to between −130°C and −150°C at each ablation line.The LA lesions comprised three lines for the left atrium, and three for the right atrial wall, according to the Cox IV pattern (Ahlsson et al., 2012).
RF ablation was performed using the Cardioblate ® BP2 Irrigated Bipolar Surgical Ablation System (Medtronic Inc.).This system uses irrigation and impedance-based power adjustments to reach tissue temperatures between 50°C and 80°C during ablation.Each line was subjected to three complete ablation periods.The right and left pulmonary vein orifices were isolated pairwise and epicardially on bypass.The remaining lines were performed endocardially upon cardioplegic arrest, according to the Cox IV pattern (Benussi et al., 2010).The biatrial lesion set was similar for both procedures.

| Echocardiographic protocol
All transthoracic echocardiography examinations were performed by the same technician using the Vivid E95 ultrasound system (GE Medical System).Stored images were analyzed offline by an experienced reader, blinded to the type of surgery.Echo parameters were measured following the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging (Badano et al., 2018).

| 2DE
Left ventricular (LV) volumes and ejection fraction (EF) were calculated using the biplane Simpson's method.We extracted the peak velocity of the early mitral inflow (E) and the late inflow caused by atrial contraction (A).The mean value of peak early diastolic tissue velocity from the septal and lateral wall (E′) on tissue Doppler imaging (TDI) was used to calculate the E/E′ ratio.The LA volume index (LAVI) was measured, using the biplane Simpson method, and indexed for body surface area (BSA).We also determined the right ventricular (RV) size and function based on tricuspid annular plane displacement (TAPSE) and systolic tissue Doppler velocity (S′).
Strain analysis was performed based on 2D speckle tracking, to measure global longitudinal LV strain by automated functional imaging (AFI) in the 4-, 3-, and 2-chamber views.LA longitudinal strain was extracted from the 4 chamber-view using the new LA strain software (Echopac LA AFI; GE Health).The zero reference was set at LV end-diastole (Figure 2).Image acquisition and analysis were performed according to EACVI/ASE Taskforce (Badano et al., 2018).
The measurements were averaged over three cardiac cycles.
Heart rhythm, height, and weight for BSA calculation were collected at the echocardiography examination.

| 3DE
Preoperatively, most of the patients were in AF where variable R-R interval enables multibeat 3D acquisition.Full-3D image acquisition was therefore performed only at the follow-up examination 1 year after surgery.The acquisition of a multibeat data set (two to four consecutive beats), at a resolution of >20 frames per second, was performed from the apical view using a real-time 3DE system.We extracted the LA maximum volumes at end systole (ES), minimum at end diastole (ED), and preceding atrial contraction (pre-A).We then calculated the reservoir fraction (ResF) ES-ED/ES, conduit (CF) ES-preA/ES, and booster fraction (BF) preA-ED/PreA.Image analysis and measurement were performed offline using standard software (EchoPAC 202; GE Healthcare).A recently developed LA-dedicated software package was used for LA 3D analysis (Echopac 4D Auto LAQ; GE Health).
Results are expressed as mean and standard deviation (SD) for echocardiographic continuous variables, which were reasonably normally distributed.Categorical variables were presented as median (25th to 75th percentile) or count (percentage).Between-group differences were evaluated using the Student's paired t-test for continuous data.Fisher's analysis was used for categorical data.A p < 0.05 was considered statistically significant.The correlation

| Study population
Of the 105 patients included in this study, 89 underwent echocardiographic examination at the 1-year follow-up (384 ± 24 days).Ten patients declined examination, and six patients died before the 1-year follow-up (three in the RF group, two Cryo group, and one NoMaze group).We excluded nine patients (three in each group) who required postoperative implantation of a Dual-Chamber permanent pacemaker device, as well as those who were in junctional rhythm (n = 4).At follow-up, 27 patients were in AF (five in the Cryo group, six RF group, 16 NoMaze group).In the absence av documented arrhythmia beyond the blanking period of 6 months, we defined the patient as being in SR at the follow-up based on 12-lead ECG and during echocardiography examination.The final analysis included 49 patients in SR (20 in the Cryo group 20; 22 RF group, and seven NoMaze group).The need for mitral valve replacement or repair was evenly distributed.

| Clinical characteristics of patients with restored SR 1-year postoperatively
All groups had comparable preoperative clinical characteristics, except for the slightly older age in the Cryo group compared with the RF group (Table 1).Of the 49 patients, 11 were women (22.4%): five in the Cryo group, four RF group, and two NoMaze group.Mitral valve replacement with a biological prosthesis was performed in one patient in each maze group and two patients in the NoMaze group.The remaining patients had a mitral repair by valvular resection with or without Neochordae plus annuloplasty.Tricuspid valve repair was performed in 29 patients in the maze groups and four in the NoMaze group.Aortic valve replacement was performed in two patients in each maze group (Table 1).

| Preoperative echocardiographic findings
Preoperative left and right ventricular size and function, and biatrial size, were comparable between patients who underwent maze ablation and those in the NoMaze group and when comparing the Cryo and RF ablation groups (Table 2).LA function assessed by LA emptying fraction and 2D reservoir strain was comparable in all groups.Eleven patients [four RF (18%), four Cryo (20%), and three NM (42%)] were in SR preoperatively.The 2D strain during the conduit and the contraction phase was comparable between groups (Table 2).

| Postoperative echocardiographic findings
At 1-year postsurgery, three cases showed more than moderate mitral valve regurgitation.As this could affect the atrial size and function, these three patients were excluded from the postoperative analysis.The analysis of 3-DE acquisition was not possible in five patients (two RF, two Cryo, and one NoMaze).Echocardiographic examination in patients with restored SR at 1 year after surgery revealed significant LV size reduction, with an LV end-diastolic volume index of 65 ± 24 mL/m 2 before surgery compared to 54 ± 13 mL/m 2 postoperatively (p = 0.004).Table 3 displays
Table 3 presents additional echocardiographic data.

| Atrial systolic function after maze surgery
Reservoir and booster function analysis showed significant difference in favour of the RF procedure.Similarly, longitudinal 2D strain analysis showed higher strain during reservoir and contraction phases in RF patients compared to Cryo (Table 3).The peak A wave velocity was 0.53 ± 0.20 m/s at follow-up.It was close to 0 in three patients (7%), and slightly higher in the RF group than the Cryo group (0.58 ± 0.18 vs. 0.46 ± 0.2 m/s; p = 0.06).We observed a moderate correlation between peak A velocity and LA booster function (r = 0.41, p ≤ 0.05).LA emptying fraction showed no significant difference between groups (Table 3).

| Atrial size and function in NoMaze patients with restored SR
In the NoMaze group, seven of 23 patients (30.4%) had SR at follow-up.
Patient showed a reduction in LA size after surgery.Preoperative LAVI was 91 ± 38 mL/m 2 compared to 74 ± 24 mL/m 2 after surgery (p = 0.01), with no difference between the maze and NoMaze groups.

| DISCUSSION
To our knowledge, this is the first prospective and randomized study to compare the effects of surgical Cryo-ablation with RF modality on the atria, assessed by 2D and 3D echocardiography.We found that patients who were in SR at 1 year after the maze procedure with concomitant mitral valve surgery presented with (1) a reduction of LA volume on 2D which was more pronounced after RF ablation compared to Cryo and (2) better systolic LA function after RF ablation expressed on 2D strain and 3DE during reservoir and contraction phase compared to the Cryo cohort, and (3) a lower booster fraction compared to the NoMaze group.
The maze procedure is performed to electrically isolate the atria by generating linear scars through the application of a warm or cold energy source.Its safety has been proven by several studies (Ad et al., 2019;Saint et al., 2013;Rankin et al., 2018), and SR restoration after this procedure has positive impacts on long-term clinical outcomes (Kim et al., 2010;Park et al., 2014), although further investigation is needed to determine the extent of LA reverse remodelling and atrial function improvement.Atria undergo a stunning phase directly after cardioversion (Khan, 2003) and lone (surgical or percutaneous) correction of MR results in LA reverse remodelling (Marsan et al., 2011) during the early postprocedural period (Chipeta et al., 2016), with a tendency to subsequently return to baseline levels in patients with untreated AF (Kawaguchi et al., 1996).
The setting becomes more complex when adding surgical ablation distress.Atrial myocardial contraction restoration might be more vulnerable when ablation lines are added to the surgical scars.
Abbreviations: BSA, body surface area; LA, left atrium; LA EmF, LA emptying fraction on 2D echo (LA maximum-LA minimum volume/LA maximum volume); LV, left ventricle; RA, right atrium; RV, right ventricle; S′, systolic tissue Doppler velocity in RV; TAPSE, tricuspid annular plane displacement.a LA conduit and contraction strain in patients in sinus rhythm.
In patients with preoperative AF and mitral valve disease who undergo lone MV surgery, spontaneous SR recovery occurs in 10%-20% of cases (Kernis et al., 2004;Lee et al., 2009).
In our cohort, SR was restored in 14% of patients who underwent surgery without AF treatment, compared to 65% in the maze group.Despite the complex geometry and the thin atrial wall, the quantification of atrial myocardial deformation using strain analysis to evaluate the phasic atrial function, was shown to be feasible, in line with other studies (Pathan et al., 2017;Gan et al., 2018) 4.1 | Effect of RF versus cryo ablation on LA size and function The two maze groups showed, from similar preoperatively indexed values, a significant reduction of LA size, with a greater reduction and better preserved atrial function in the RF group.
We tested the hypothesis that Cryo ablation has a greater negative impact on atrial function compared to RF, which is supported by the fact that Cryo lesions seem to cause wider damage on the atrial wall (Boano et al., 2020).The result might reflect the T A B L E 3 Echocardiographic variables 1 year after surgery.In our study, the feasibility of LA acquisition and analysis on 3D echocardiography was good (90%) and showed 1 year after MV surgery and maze, LA volumes were still more than moderately enlarged.This enlargement likely reflects the structural remodelling process in response to the volume and pressure overload caused by the preoperative duration and severity of mitral disease, as well as the AF burden.LV diastolic function may impact LA size and function.
Preoperative assessment of diastolic function is challenging in the presence of severe MR and AF.Postoperatively, we found no difference in diastolic parameters expressed as E/E′, and the right ventricular systolic pressure was comparable between ablation groups.Furthermore, we found no difference in LA conduit function, which is closely related to passive LV filling and LV compliance (Thomas & Abhayaratna, 2017).
LV function has been reported to improve after mitral surgery with concomitant ablation in patients with impaired function at baseline (Kim et al., 2015).Most of our patients had a good systolic ventricular function before the procedure, and they maintained comparable systolic function postoperatively.

| Booster function in NoMaze compared to Maze patients
Compier et al. reported that atrial active transport function is not restored in approximately half of the patients with postprocedural SR after concomitant surgical limited LA RF ablation, while it was restored in patients who underwent bare pulmonary vein isolation (Compier et al., 2017).
In parallel, our present study showed that compared to ablated patients, nonablated patients with spontaneous SR recovery showed better LA active contraction recovery on both 2D and 3D echocardiography when the regurgitation was corrected, and no atrial wall distress was added by freezing or warming.However, the different preoperative AF burden between Maze and NoMaze groups adds a certain complexity to the interpretation of these results.

| CONCLUSIONS
In patients with restored SR 1 year after concomitant mitral valve surgery and Cox-maze IV ablation, the RF modality had a more positive impact on atrial mechanical function compared to the Cryo method.The availability of 3DE, and measurement of LA phasic function, provide a reliable tool for determining therapy results, and could become a precious technique for assessing LA function in clinical practice.

| Study limitations
The follow-up period was limited to 1 year.Further LA evaluation based on a larger number of patients, and with longer follow-up, would be valuable in the future.NoMaze patients were not randomized, in accordance with the guidelines, because of their high baseline risk.We did not perform any electro-anatomic voltage mapping after the ablation procedure was completed.SR restoration was defined as the absence of documented arrhythmia during the last 6 months previous follow-up, confirmed by 12-lead ECG and echocardiography at 1-year examination.We do not have though a complete overview of the durability and stability of the restored SR.
was assessed using Pearson's correlation coefficient.No corrections were performed for multiple comparisons.The intraclass correlation coefficient (ICC) and 95% confidence interval based on two-way mixed average measures were used to assess the reliability of 3D volume measurements performed by two observers (JK and MÅA) and by the same observer (MÅA) two times on separate occasions 3 weeks apart, in a random sample of 10 patients.
data from the NoMaze and the maze groups.

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I G U R E 2 (a) Left atrial function analysis by 2D strain.(b) Left atrial volume and function using 3D echocardiography.2D, twodimensional; 3D, three-dimensional.
different breadth of atrial myocardial injury during the ablative procedure between the two energy sources.Direct application of a cooled probe on the atrial epicardium leads to the formation of frozen tissue in which trapped cells become irreversibly damaged and are ultimately replaced by fibrous tissue.The width of this area can vary depending on the atrial wall thickness, the time of application, and the temperature achieved.Our Cryo probe reached temperatures of −150°C.Currently available devices that cool down to higher temperatures might have the advantage of causing less damage to the surrounding tissues.The RF lesion produced by tissue heating is smaller and more distinct upon gross examination.The temperature reached is over 50°C, which generates a central zone of coagulative necrosis, with denaturation of most intracellular proteins.These areas develop inflammatory infiltrates, which are replaced by fibrosis(Gage et al., 2009).The impaired atrial function could indicate an increased fibrotic burden of the atria, resulting from the larger lesions caused by Cryo ablation, which may irreversibly affect atrial mechanical properties.Kim et al. found a higher atrial contractility restoration rate after Cryo than after RF ablation(Kim et al., 2018).The authors used, however different lesion in this retrospective study, and atrial contraction recovery was analyzed on 2D echocardiographic parameters based only on atrial wave velocity.

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G U R E 3 Left atrial reverse remodelling after surgery is related to the duration of atrial fibrillation.Left atrial volume index (LAVI) difference between preoperative and postoperative measurements.Y-axis is relative number of patients in %.F I G U R E 4 Left atrial reservoir, conduit, and booster pump function assessed by 3-dimensional echocardiography in patients with sinus rhythm 1 year after Cox-Maze IV concomitant with mitral valve surgery.Y-axis is mean atrial function values expressed in %.