Radiofrequency catheter ablation combined with spironolactone in the treatment of atrial fibrillation: A single‐center randomized controlled study

Abstract At present, the question of whether radiofrequency ablation (RFA) combined with spironolactone can reduce the levels of plasma angiotensin II (AngII) and aldosterone (ALD) in patients with atrial fibrillation (AF) and reduce the recurrence of AF has not been reported. Hypothesis The present study evaluates the effect of spironolactone as an ALD antagonist on the short‐term and long‐term recurrence of AF after RFA. A total of 203 patients were enrolled in the present study, with 102 patients in the spironolactone therapy group (Group PVI/SP) and 101 patients in the control group (Group PVI alone). The AngII and ALD levels and the size of the left atrium in patients with AF were observed in order to evaluate the relationship between the combination therapy of spironolactone with RFA and the success rate in AF treatment. After therapy, the levels of AngII (52.8 vs. 64.3 pg/ml, p < .001), ALD (45.7 vs. 60.6 pg/ml, p = .016), and N‐terminal of B‐type natriuretic peptide (NT‐proBNP) (73.5 vs. 110 pg/ml, p = .016), along with the size of the left atrium (35.8 vs. 37.2 mm, p = .007), were all significantly lower in Group PVI/SP compared with Group PVI alone. The cumulative AF‐free survival rate was higher in Group PVI/SP than in Group PVI alone after treatment (85.3% vs.73.3%, p = .033). In RFA combined with spironolactone treatment, spironolactone can directly antagonize the effects of ALD and AngII and the recurrence of AF and improve left ventricular function.

AF. 2 The activation of the renin-angiotensin-aldosterone system (RAAS) is involved in the structural remodeling of the atrium, primarily through the activation of angiotensin II (AngII) and aldosterone (ALD). 3 A previous study has suggested that spironolactone, an ALD receptor antagonist, is able to reduce the level of ALD in patients with AF, as well as inhibiting atrial fibrosis, thus reducing the recurrence of AF. 4 At present, the question of whether radiofrequency ablation (RFA) combined with spironolactone can reduce the AngII and ALD levels in patients with AF, and thus reduce the recurrence of AF, has not been reported. The present study is a single-center prospective randomized study with the purposes of investigating the effect of spironolactone combined with RFA on the plasma AngII and ALD levels and the left atrium size in patients with AF and evaluating the relationship between this combination therapy and the success rate of AF treatment, so as to provide further clinical therapeutic investigation on increasing the success rate of AF treatment through the use of RFA procedures.

| Objects
The 379 patients with symptomatic AF treated by radiofrequency catheter ablation were enrolled. Among these patients, 215 met the inclusion criteria. The inclusion criteria were as follows: (1) patients with an age of ≥18 and ≤ 80 years old; (2) patients with paroxysmal or persistent AF (duration ≤12 months) who were to be treated by radiofrequency catheter ablation; (3) patients with grade I, II, or III New York Heart Association (NYHA) heart function before ablation; and (4) patients who had not been treated with spironolactone within 1 month prior to enrollment. The exclusion criteria were as follows: (1) patients with an age < 18 or > 80 years old; (2) patients with grade IV NYHA heart function before ablation; (3) patients with persistent AF lasting more than 12 months; (4) patients who did not achieve the intended surgical goals due to complications; (5) patients in whom AF continued after CA ablation and who were unable to convert to sinus rhythm after direct current synchronous cardioversion on the body surface, thus requiring additional ablation (such as linear ablation and fragment potential ablation) during CA ablation; (6) patients who could not follow up according to the specified timetable after the operation; (7) patients who were treated with spironolactone within 1 month prior to enrollment; and (8) patients who were treated with spironolactone within 1 month prior to enrollment.
The design of the present study was reviewed and approved by the Ethics Committee of the Affiliated Union Hospital of Fujian Medical University (approval No. 2011CXKT001). All patients signed an informed consent before RFA and agreed to receive follow-up examinations in accordance with the study's design.

| RFA methods
Local anesthesia was applied in all cases. The left and right femoral veins were punctured, and a 10-electrode catheter was inserted through the left femoral vein to enter the coronary sinus. The atrial septum was punctured twice through the right femoral vein, and two 8F preface sheaths were sent into the left atrium. Through the preface sheaths, nonselective left and right pulmonary venography was performed to show the opening and line of each pulmonary vein.
A 10-pole annular catheter (Lasso, BioSense Webster) and 3.5 mm saline perfusion catheter (Thermo-cool Navistar, BioSense Webster) were sent to the left atrium through the preface sheath. Under the guidance of the mapping system (CARTO 3, BioSense Webster), the Lasso catheter was used to construct a three-dimensional structure of the left atrium. The Lasso catheter was sent into each pulmonary vein to measure the vein's potential. The position of each pulmonary vein opening and its potential characteristics were marked based on the three-dimensional structure of the left atrium. The preset ablation power was within 25~35 W, and the temperature was set at 43 C. The perfusion volume of normal saline during ablation was 17 ml/min. Linear ablation was performed around the ipsilateral pulmonary vein, 5-10 mm away from the pulmonary vein opening.
The electrical isolation of the pulmonary vein was the end point of ablation.
In patients with paroxysmal AF, the end point of the operation occurred either after the electrical isolation of the pulmonary vein with the intravenous injection of isoproterenol, which increased the patient's heart rate by 30% or more above the basal heart rate, or the confirmation that electrical conduction between the bilateral pulmonary vein and left atrium was not recovered, and 280-160 ms stimulation at the proximal end of the coronary sinus could not induce AF, atrial flutter (AFL), atrial tachycardia (AT), or other rapid atrial arrhythmias. In patients with persistent AF, if the AF was terminated and the sinus rhythm was restored after bilateral pulmonary vein isolation, the end point of the operation was the same as that in patients with paroxysmal AF. In patients with persistent AF, if the AF could not be terminated after bilateral pulmonary vein electrical isolation, 150 mg of amiodarone was injected intravenously, and the patient was then treated with direct current synchronous cardioversion with 150-200 J via the body surface. In patients who were able to maintain the sinus rhythm, the end point of the operation was the same as that in patients with paroxysmal AF. Linear ablation of the top of the left atrium, mitral annulus, and isthmus of the tricuspid annulus was necessary for patients who could not maintain sinus rhythm or whose AFL and AF could be induced by 280-160 ms stimulation of the proximal end of the coronary sinus; these patients were excluded.

| Postoperative follow-up
All patients were followed up monthly for 12 months via outpatient visits or telephone calls. If the patient had any discomfort, he/she could also contact the doctor by telephone, information message, WeChat, etc. for additional follow-up and to check the ECG and/or 24 h ambulatory electrocardiogram. A CA ablation was considered successful if the patient experienced no AF or tachycardia lasting more than 1 min during the follow-up period. The first 3 months after CA ablation was designated as the blank period, during which a recurrence of AF, AFL, or AT was considered an early recurrence. A recurrence of AF, AFL or AT during the 3 to 12 months after ablation was considered a late recurrence. The levels of AngII, ALD, N-terminal of B-type natriuretic peptide (NT-proBNP), and transthoracic echocardiography were monitored in all patients before and 3 months after CA ablation ( Figure 1).

| Drug therapy after CA ablation
Routine anticoagulant treatment was carried out for 3 months after CA ablation. After 3 months, the decision of whether to continue anticoagulant treatment was made jointly by the follow-up physician and the patient based on the patient's CHA 2 DS 2 -VASc score. The antiarrhythmic drugs propafenone or amiodarone were routinely used for 3 months after CA ablation. After 3 months, the antiarrhythmic drugs could either be stopped or continued depending on whether the patient had rapid atrial arrhythmia. If necessary, the follow-up physician was free to treat the patient with the angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB).

| Grouping of patients
The patients were randomly divided into two groups according to the order of treatment and the random number table method. The spironolactone treatment group (Group PVI/SP) was given 20 mg of spironolactone orally once a day for 3 months. The control group (Group PVI alone) was not given spironolactone.

| Statistical analysis
All data analysis was based on the principle of intention analysis. The Kolmogorov-Smirnov test was used to verify whether the data followed the normal distribution. The normal distribution data were represented by x± s, and a t test was used to compare the differences between the groups. The non-normal distribution bias data were represented by the median (25%, 75%), and non-parametric testing was used to compare the differences between the groups. The enumeration data were expressed in cases (%) and tested by χ 2 or the Fisher exact probability method. The Kaplan-Meier survival analysis and the log-rank test were used to evaluate the differences in postoperative AF-free survival time. All analyses were processed by SPSS 22.0 statistical software, and p < .05 (bilateral) was considered statistically significant. There was no significant difference in the baseline data between the two groups (Table 1).

Change in the AngII level in the two groups during follow-up:
There was no significant difference in the AngII level between Group PVI/SP and Group PVI alone (59.7 vs. 63.3 pg/ml, p = 0.182) before ablation. At 3 months after ablation, the AngII level had decreased significantly in Group PVI/SP compared with Group PVI alone (52.8 vs. 64.3 pg/ml, p < .001). The difference in the AngII level before and after CA ablation (ΔAngII) in Group PVI/SP was À6.2(À16.9-À0.5) pg/ml, and the difference was statistically significant (p < .001), while the ΔAngII in Group PVI alone was 1.0(À9.2-13.5) pg/ml (p = 0.279). The difference in ΔAngII between the two groups was statistically significant (p < .001) ( Table 2).
3. Change in the ALD level in the two groups during follow-up: There was no significant difference in the ALD level between Group PVI/SP and Group PVI alone before ablation (61.1 vs. 59.0 pg/ml, p = 0.829). At 3 months after ablation, the ALD level had decreased significantly in Group PVI/SP compared with Group PVI alone (45.7 vs. 60.6 pg/ml, p = .016). The difference in the ALD level before and after ablation (ΔALD) in Group PVI/SP was À11.4(À32.6, À1.1) pg/ml, p < .001, while the ΔALD in F I G U R E 1 Flowchart of the patient's treatment follow-up Group PVI alone was 1.5(À14.9, 12.4) pg/ml, p = 0.674. The difference in ΔALD between the two groups was statistically significant (p < .001) ( Table 2) The difference in the NT-proBNP level before and after ablation (ΔNT-proBNP) in Group PVI/SP was À87.0 pg/ml (p < .001), while the ΔNT-proBNP in Group PVI alone was À21.00 pg/ml (p = .003). The difference in ΔNT-proBNP between the two groups was statistically significant (p = .003) ( Table 2).     The transmural myocardial injury caused by catheter ablation must initiate the repair process of the myocardial injury. The scope of F I G U R E 2 Comparison of cumulative atrial fibrillation-free survival between two groups of patients the injury repair increases with an increase in the size of the site of the ablation injury, and the process of damage repair is self-limited.
As long as the factors that cause the damage are removed, the repair will automatically terminate and will not continue to exist. If the ablation scope in the atrium is too great, the damage repair process will have an impact on atrial muscle fibrillation. All patients in this study underwent CPVI ablation without any additional ablation (e.g., linear ablation, matrix ablation, CFAES ablation or GP ablation). The degree of damage caused by atrial ablation and the degree of damage repair after ablation are comparable.
Renin-angiotensin system (RAS) inhibitors significantly reduce the recurrence of atrial fibrillation in patients following catheter ablation (OR, 0.61; 95% CI, 0.45-0.82). 5 The arrhythmogenic substrate of AF is driven by atrial fibrosis, 6 and AF itself also promotes atrial fibrosis. 7 ALD binding to the mineralocorticoid receptor and subsequent cardiac fibrosis formation is strongly associated with increased AF propensity. 8  The structural remodeling of the atria manifested mainly as atrial fibrosis and atrial enlargement. The left-atrial size is also an important predictor of the recurrence of atrial fibrillation after cardioversion treatment. 12 The results of this study showed that in Group PVI alone, there was no difference in the AngII and ALD serum levels 3 months after CA ablation operation, and there was no difference in the size of the left atrium. This indicates that the repair process of the myocardial injury caused by catheter ablation had no effect on the process of atrial fibrosis, and the catheter ablation itself did not increase the atrial fibrosis.
One meta-analysis by Zhao suggested that RAS inhibitors were of significant benefit in reducing the recurrence rate of AF after catheter ablation. 5  which is shown as an increased LVEF and decreased NT-proBNP serum level.
The limitations of the present study: 1. Although a prospective randomized study design was adopted for the present study, the sample size was small, and it involved data analysis from a single center, which could lead to a certain degree of bias.
2. In the present study, the therapeutic course of spironolactone was only 3 months in duration, and so it was impossible to evaluate the most appropriate therapeutic course for spironolactone after RFA.
3. The side effects of spironolactone, such as hyperkalemia and hyperplasia of the mammary gland, were not observed in the present study, which could not provide an analytical basis for the safety of spironolactone treatment.
4. The follow-up method adopted in the present study involved regular follow-ups plus telephone follow-ups when necessary; thus, it is inevitable that a small number of asymptomatic AF events were missed. The most appropriate dosage and course of treatment and the safety of the combination of spironolactone and RFA for AF are questions that need to be addressed in future studies.

| CONCLUSION
In the combination therapy of RFA and spironolactone, spironolactone can directly antagonize the effects of ALD and AngII, reverse the electrical and structural remodeling of the atrium caused by the above two factors, reduce the diameter of the left atrium and the occurrence of AF, and improve the left ventricular function in patients with AF.

CONFLICT OF INTEREST
The authors declare that they have no competing interests.

AUTHORS CONTRIBUTION
Weiwei Wang and Jianhua Chen conceived the idea and conceptualized the study. Feilong Zhang and Xuehai Chen collected the data.
Xuehai Chen, Xudong Sun and Jinguo Li analyzed the data. Weiwei Wang and Jianhua Chen drafted the manuscript, then and Lianglong Chen reviewed the manuscript. All authors read and approved the final draft.

DATA AVAILABILITY STATEMENT
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.