Long-term Outcomes after Second-Generation Cryoballoon Ablation of Atrial Fibrillation and Analysis of Risk Factors Related to Recurrence : Cardiology Discovery

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Special Issue for Coronary Bifurcation Lesions, Guest Editor, Shaoliang Chen: Original Articles

Long-term Outcomes after Second-Generation Cryoballoon Ablation of Atrial Fibrillation and Analysis of Risk Factors Related to Recurrence

Dai, Yufan1; Wang, Chenyuan2; Wang, Zulu1,*; Liang, Ming1; Yang, Guitang1; Jin, Zhiqing1; Ding, Jian1; Zhang, Ping1; Han, Yaling1

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doi: 10.1097/CD9.0000000000000070
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  • This study provides data on the 3-year recurrence rate of 760 patients with drug-refractory symptomatic atrial fibrillation (AF) undergoing pulmonary vein isolation using second-generation cryoballoon in large center in China.
  • Long AF course and weight gain after ablation were independent risk factors for recurrence.


  • Considering that the course of disease is an independent risk factor for recurrence of AF, surgical treatment should be performed as soon as possible after the diagnosis of AF.
  • It is suggested that more attention should be paid to post-operative weight management in patients with AF.


Pulmonary vein isolation (PVI) has been recognized as the cornerstone of catheter ablation of atrial fibrillation (AF). As a single-shot PVI technique, cryoballoon ablation (CBA) has become one of the standard approaches of PVI.[1] In recent years, a second-generation cryoballoon (CB2, Arctic Front Advance, Medtronic, Minneapolis, Minnesota, USA) with extension of the cryogenic delivery area to the distal hemisphere became commercially available.[2] Single-center studies with 1-year follow-up have evaluated clinical outcomes using CB2 with freedom from recurrence at ~80% in paroxysmal AF (PAF)[2–9] and 60%–70% in persistent AF (SAF).[10–12] However, there are limited long-term data regarding the efficacy and procedural safety.[13–17] The present study reports long-term data in patients with PAF and SAF treated with CB2 in our center.


Patient population

From August 2016 to December 2018, 760 consecutive patients with AF were ablated with CB2 in the Department of Cardiology, General Hospital of Northern Theater Command, including 462 (60.8%) males and 298 (39.2%) females. The average age was (59.4 ± 10.4) years old, and the average CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65–74 years, sex category) score was 1.72 ± 1.48. There were 547 (72.0%) cases of PAF and 213 (28.0%) cases of SAF. The duration of pre-operative AF in patients with SAF ranged from 8 days to 48 months, with an average of 3.9 months (median of 2.0 months). A total of 748 patients, including 539 with PAF and 209 with SAF completed the follow-up.

The inclusion criteria were (1) history of AF with evidence of 12-lead electrocardiogram (ECG) or Holter-ECG, (2) symptomatic AF that failed to respond to at least 1 membrane-active anti-arrhythmic drug, and (3) catheter ablation of AF for the first time. The exclusion criteria were (1) presence of left atrial (LA) thrombus on trans-esophageal echocardiography (TEE) before the procedure, (2) intolerant to anticoagulation therapy, (3) hyperthyroidism without treatment, (4) severe valvular disease or advanced heart failure, or (5) concomitant supra-ventricular tachycardia, pre-excitation syndrome, typical atrial flutter (AFL), or other arrhythmias that required radiofrequency catheter ablation at the same procedure.

All procedures involving humans were approved by the ethical review board at the General Hospital of Northern Theater Command, Shenyang, China (Y(2020)090), and follow the 1964 Declaration of Helsinki and its later amendments. Informed consent was obtained from all participants.

Preoperative preparation and anticoagulant therapy

Routine biochemical examinations and auxiliary examinations were performed for all patients before the procedure. Routine transthoracic echocardiography was performed to evaluate cardiac structure and function. TEE was used to assess the presence of intracardiac thrombus. Computed tomography angiography of the heart and pulmonary veins, combined with simultaneously oral contrast esophageal radiography was performed to evaluate the size and shape of left atrium and pulmonary veins and the anatomical relationship between the left atrium, pulmonary veins, and esophagus. Anticoagulant therapy (the overwhelming majority of patients receiving rivaroxaban or dabigatran etexilate) was given to all patients before ablation and at least 2 months after ablation.

Cryoballoon ablation procedure

The procedure was performed under deep sedation using fentanyl and/or midazolam, and peripheral arterial blood pressure and oxygen saturation were continuously monitored. Coronary sinus catheter and quadrupolar or bipolar catheter were placed via right internal jugular vein and left or right femoral vein respectively. Trans-septal catheterization was performed via the right femoral vein, then the trans-septal sheath was replaced with a 15-F OD steerable sheath (FlexCath Steerable Sheath; Medtronic, Minneapolis, Minnesota, USA). A CB2 with an Achieve mapping catheter was advanced through the FlexCath sheath into the left atrium.

All patients underwent the procedure with the large 28-mm CBA. The order of freezing is usually left superior, left inferior, right inferior, and right superior pulmonary vein. Typically, a minimum of twice cryoballoon freezes (each time does not exceed 180 seconds, and the minimum temperature during ablation is not less than −55°C) was performed at the ostium of each pulmonary vein. Pulmonary vein potentials were recorded before and after cryoablation with the Achieve catheter positioned so that the operators could evaluate PVI. For target pulmonary veins that CBA could not fully isolate, radiofrequency catheter ablation was used until PVI was reached. If other possible ectopic trigger foci (such as the superior vena cava) or typical AFL was found during the procedure, a radiofrequency catheter was used for ablation.

Post-procedural care and clinical follow-up

Follow-up was done by telephone, outpatient visit, and/or WeChat/short messages after discharge. All anti-arrhythmic drugs were stopped after a 3-month blanking period after the procedure, and patients were followed up at 3, 6, and 12 months and annually thereafter with a 12-lead ECG and/or ambulatory monitoring. Further ECG and/or ambulatory monitoring was prompted by symptoms. AF recurrence was defined when there was a documented episode of atrial arrhythmias, including AF, AFL, and/or atrial tachycardia (AT) lasting >30 seconds after the blanking period of 3 months. Adverse events, medication compliance of anti-coagulants and anti-arrhythmic drugs, body weight change (the difference between the body weights during AF ablation and at the time of AF/AT recurrence or at follow-up in patients without recurrence) were recorded.

Statistical analysis

All calculations were performed with the statistical analysis software SPSS 19.0 (IBM Corp., Armonk, New York, USA). Count data, measurement data, and ordinal data were compared by χ2 tests, t tests, and non-parametric tests, respectively. Multivariate analysis was carried out with binary multivariate Cox regression. Differences were considered statistically significant at P < 0.05.


Acute ablation outcome

Acute PVI was achieved in all of the 760 patients in this study. Radiofrequency catheter application for additional focal or gap ablation was needed to achieve PVI in 11 (1.4%) patients for 14 (0.5%, 14/(760 × 4)) pulmonary veins. Typical AFL was successfully ablated in 10 (1.3%) patients at the same procedure. The rate of major complications was 7 (0.9%). Pericardial tamponade occurred in 1 patient during the procedure which resolved after pericardiocentesis and drainage. Transient phrenic nerve paralysis occurred in 6 (0.8%) cases during right superior pulmonary vein freezing, and all cases recovered during the procedure after rapid cessation of cryoablation. The average number of freezes per case were 2.0 ± 0.4. The average procedure time was (72.0 ± 29.0) minutes. The average X-ray exposure time was (19.9 ± 9.5) minutes, and the average amount of X-ray exposure was (478 ± 499) mGy. During the perioperative period, there were no adverse events such as stroke, transient ischemic attack, massive hemorrhage requiring blood transfusion, pulmonary vein stenosis, left atrioesophageal fistula, myocardial infarction, or death.

Analysis of success rate after CBA of AF

Up to December 2019, among the 760 patients with CBA, only 12 (1.6%) were lost to follow-up, 748 patients were followed up ≥1 year, 374 patients ≥2 years, and 80 patients ≥3 years. The mean follow-up duration was (19 ± 8) months. Freedom from AF/AFL/AT was achieved in 75.0% (561/748) of patients at 12 months, 68.7% (257/374) at 24 months, and 62.5% (50/80) at 36 months. The success rate was 75.0% for PAF and 75.1% for SAF at 12 months follow-up, 69.4% for PAF and 67.4% for SAF at 24 months follow-up, and 63.2% for PAF and 60.9% for SAF at 36 months follow-up, with no significant differences between PAF and SAF groups at any time point.

During follow-up, 28 patients with AF/AT recurrence underwent revision procedures, and the CARTO 3 mapping system was used in all 28 patients. Eighty-five percent of recurrent patients received anti-arrhythmic drugs including propafenone, amiodarone, sotalol, and/or beta-blockers.

Predictors of recurrence after ablation

Predictors of recurrence in the univariate analysis

The patients were divided into non-recurrence and recurrence groups according to the follow-up results after AF ablation. The baseline data, intra-operative data, and post-operative follow-up data of the 2 groups were statistically analyzed [Table 1]. The univariate analysis showed that AF course (P < 0.001), anteroposterior diameter of the left atrium (P = 0.04), and body weight gain rate (P < 0.001) were predictors of recurrence [Table 1].

Table 1 - Predictors of recurrences in the univariate analysis after CB2 ablation in AF patients
Variable Non-recurrence (n = 513) Recurrence (n = 235) t/Z/χ 2 P
Male, n (%) 327 (63.7) 133 (56.6) 3.47 0.06
Age (years), mean ± SD 59.3 ± 10.4 59.9 ± 10.6 0.72 0.47
AF course (years), mean ± SD 46.8 ± 51.1 68.2 ± 68.1 4.78 < 0.001
PAF, n (%) 372 (72.5) 167 (71.1) 0.17 0.68
Height (cm), mean ± SD 169.1 ± 8.1 168.6 ± 8.6 −0.80 0.43
Weight (kg), mean ± SD 73.0 ± 11.8 72.7 ± 12.6 −0.25 0.80
BMI (kg/m2), mean ± SD 25.5 ± 3.4 25.4 ± 3.5 −0.21 0.83
Heart failure, n (%) 10 (1.9) 5 (2.1) 0.01 0.90
Hypertension, n (%) 232 (45.2) 105 (44.7) 0.02 0.89
Stroke, n (%) 56 (10.9) 35 (14.9) 2.39 0.12
DM, n (%) 84 (16.4) 39 (16.6) 0.006 0.94
Vascular disease, n (%) 19 (3.7) 3 (1.3) 3.33 0.07
Coronary artery disease, n (%) 58 (11.3) 23 (9.8) 0.39 0.54
CHA2DS2-VASc score, mean ± SD 1.7 ± 1.4 1.8 ± 1.6 1.49 0.14
Creatinine (μmol/L), mean ± SD 72.5 ± 15.1 71.0 ± 15.7 −1.25 0.21
Creatinine clearance (mL/min), mean ± SD 97.2 ± 27.7 97.0 ± 27.5 −0.11 0.91
Cholesterol (mmol/L), mean ± SD 4.3 ± 0.9 4.3 ± 1.0 0.50 0.62
Triglyceride (mmol/L), mean ± SD 1.5 ± 1.0 1.5 ± 1.1 0.42 0.67
LDL (mmol/L), mean ± SD 2.7 ± 5.9 2.4 ± 0.7 −0.93 0.35
Left atrial diameter (mm), mean ± SD 37.4 ± 5.1 38.2 ± 4.9 1.96 0.04
Left ventricular end-diastolic (mm), mean ± SD 47.6 ± 4.9 47.9 ± 5.7 0.72 0.47
E peak (m/s), mean ± SD 0.8 ± 0.2 0.8 ± 0.2 0.90 0.37
A peak (m/s), mean ± SD 0.8 ± 0.2 0.7 ± 0.2 −0.72 0.47
E/A (>1/<1/=1) 88/144/12 48/59/8 2.07 0.36
LVEF (%), mean ± SD 61.2 ± 5.8 61.5 ± 5.9 0.63 0.53
TTI (n), mean ± SD 1.6 ± 1.1 1.5 ± 1.2 −1.48 0.14
Rate of body weight gain (%), mean ± SD −0.1 ± 3.6 1.9 ± 2.9 8.02 < 0.001
AF: Atrial fibrillation; BMI: Body mass index; CB2: Second-generation cryoballoon; CHA2DS2-VASc: Congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, sex category; DM: Diabetes mellitus; E/A: E peak/A peak; LDL: Low-density lipoprotein; LVEF: Left ventricular ejection fraction; PAF: Paroxysmal atrial fibrillation; TTI: Times to isolation.

Predictors of recurrence in the multivariate analysis

According to the univariate analysis results, AF course, anteroposterior diameter of the left atrium, and body weight gain rate were included in multivariate Cox regression analysis. Only AF course (P = 0.001) and body weight gain rate (P = 0.009) were independent predictors of recurrence; the anteroposterior diameter of left atrium was not (P = 0.923).


There have been many reports on the 1-year success rate of CB2 in the treatment of AF,[2–12] but there are few reports on its long-term efficacy and safety.[13–17] The present results show that CB2 ablation has a high success rate and excellent safety in the treatment of AF. The 1-, 2-, and 3-year success rates were 75.0%, 68.9%, and 62.5%, respectively.

Comparison with the previous study


There have been several reports about the success rates in PAF patients after single PVI ablation using CB2 at 1-year follow-up, which were higher than those of the first-generation CBA.[2–9] However, there are limited long-term data regarding the efficacy and procedural safety.[13–15] The STOP AF PAS study showed that CB2 ablation in patients with PAF was effective, with freedom from AF/symptomatic AFL/AT in 79.0% of patients at 12 months, 70.8% at 24 months, and 64.1% at 36 months.[14] The success rates of CB2 ablation for PAF in the present study were 75.0% at 1 year, 69.4% at 2 years, and 63.2% at 3 years, which were similar to previous results.[14] Collectively, the evidence suggests that CB2 ablation of PAF has a high success rate at 3 years after a single procedure.


Several studies have shown that freedom from atrial tachyarrhythmias was achieved in 60%–70% after single PVI ablation of SAF using CB2 at the 1-year follow-up.[10–12] Recently, the long-term success rate of second-generation CBA in the treatment of SAF has also been reported,[16,17] but there are some differences among the long-term success rates. The main reason for the discrepancies may be related to differences in patient populations and ablation strategies (predominantly PVI or PVI plus). The shorter sustained duration of AF in patients with SAF (mean 3.9 months, median 2.0 months) in the present study may be the reason for the high success rate and low recurrence rate. The results indicate that SAF patients with shorter persistent duration have similar ablation outcomes to patients with PAF, with a good curative effect in both populations.

Analysis of factors related to AF recurrence

The relationship between AF course and recurrence is consistent with most previous studies.[18–20] The influence of body weight gain rate on recurrence may be due to 3 factors[21–24]: (1) weight gain can increase epicardial fat deposition and easily lead to epicardial inflammation. The inflammatory response and a variety of inflammatory factors play an important role in AF occurrence and development; (2) adipocytes can affect the ion channels of atrial myocytes, thus changing the electrophysiological characteristics of atrial myocytes and increasing the risk of AF; (3) weight gain often causes obstructive sleep apnea and increases the risk of AF recurrence.

The increase of LA diameter has been reported as a risk factor for AF recurrence after ablation.[19,20,25] However, although enlargement of the anteroposterior diameter of the left atrium in this study was a risk factor for postoperative recurrence, it was not an independent risk factor, possibly because the degree of enlargement of the left atrium in the recurrence group was mild with an average anteroposterior diameter of (38.2 ± 4.9) mm.


Our results should be considered in the context of some limitations. First, all data were from a single center, and the results may have a certain degree of deviation. Second, the judgment of AF recurrence during follow-up was according to the symptoms, surface ECG, and 24-hour ambulatory monitoring, so the recurrence rate of AF might be underestimated without using longer monitoring methods such as 7-day ambulatory monitoring. However, the follow-up methods we used were similar to those in most clinical studies, and the results are credible and comparable. Finally, the sample size of patients with data from 3 years after ablation was relatively small, which may have influenced the judgment of the recurrence rate, but the extremely low loss to follow-up rate (1.6%) in this study compensates for this to some extent.


PVI with CB2 has a high acute success rate and good safety in the treatment of PAF and SAF, with freedom from all atrial arrhythmias at 36 months in 63.2% and 60.9% of patients, respectively. Long AF course and weight gain after ablation were independent risk factors for recurrence.



Conflicts of interest


Editor note: Yaling Han is the Editor-in-Chief of Cardiology Discovery. Zulu Wang is an Editorial Board Member of Cardiology Discovery. The article was subject to the journal’s standard procedures, with peer review handled independently of these editors and their research groups.


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Atrial fibrillation; Second-generation cryoballoon ablation; Pulmonary vein isolation; Recurrence

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