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Original research
Sex differences in mapping and rhythm outcomes of a repeat atrial fibrillation ablation
  1. Hui-Nam Pak,
  2. Je-Wook Park,
  3. Song-Yi Yang,
  4. Min Kim,
  5. Hee Tae Yu,
  6. Tae-Hoon Kim,
  7. Jae-Sun Uhm,
  8. Boyoung Joung,
  9. Moon-Hyoung Lee
  1. Division of Cardiology, Department of Internal Medicine, Yonsei University Health System, Seoul, Korea (the Republic of)
  1. Correspondence to Professor Hui-Nam Pak, Division of Cardiology, Department of Internal Medicine, Yonsei University Health System, Seoul 03722, Korea (the Republic of); hnpak{at}yuhs.ac

Abstract

Objective The risk of procedure-related complications and rhythm outcomes differ between men and women after atrial fibrillation catheter ablation (AFCA). We evaluated whether consistent sex differences existed in mapping and rhythm outcomes in repeat ablation procedures.

Methods Among 3282 patients in the registry, we analysed 443 consecutive patients (24.6% female, 58.5±10.3 years old, 61.5% with paroxysmal atrial fibrillation) who underwent a second AFCA. We compared the clinical factors, mapping, left atrial (LA) pressure, complications and long-term clinical recurrences after propensity score matching.

Results LA volume index (43.1±18.6 vs 35.8±11.6 mL/m2, p<0.001) was higher, but LA dimension (40.0±6.8 vs 41.6±6.3 mm, p=0.018), LA voltage (0.94±0.55 vs 1.20±0.68 mV, p=0.002) and pericardial fat volume (89.5±43.1 vs 122.1±53.9 cm3, p<0.001) were lower in women with repeat ablation than in their male counterparts. Pulmonary vein (PV) reconnections were lower (58.7% vs 74.9%, p=0.001), but the proportion of extra-PV triggers (27.5% vs 17.0%, p=0.026) and elevated LA pulse pressures (79.7% vs 63.7%, p=0.019) was significantly higher in women than in men. There was no significant sex difference in the rate of procedure-related complications (4.6% vs 4.2%, p=0.791). During a 31-month (8–60) median follow-up, clinical recurrences were significantly higher in women after both the de novo procedure (log-rank p=0.039, antiarrhythmic drug (AAD)-free log-rank p<0.001) and the second procedure (log-rank p=0.006, AAD-free log-rank p=0.093). Female sex (HR 1.51, 95% CI 1.06 to 2.15, p=0.023), non-paroxysmal atrial fibrillation (HR 1.78, 95% CI 1.30 to 2.34, p<0.010) and extra-PV triggers (HR 1.88, 95% CI 1.28 to 2.75, p=0.001) were independently associated with clinical recurrences after repeat procedures.

Conclusions During repeat AFCA procedures, PV reconnections were lower in women than in men, and the existence of extra-PV triggers and an LA pressure elevation were more significant, which resulted in poor rhythm outcomes.

Trial registration number NCT02138695.

  • atrial fibrillation
  • catheter ablation

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Data, analytic methods and study materials are available upon reasonable request to other researchers who want to reproduce the results or replicate the procedure.

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Introduction

The incidence and prevalence of atrial fibrillation (AF) are higher in men than in women regardless of age group.1 In female patients with AF, symptoms and quality of life are poorer and the thromboembolic risk and mortality are higher than in men.2 Nevertheless, female patients are less prone to requiring rhythm control treatment including atrial fibrillation catheter ablation (AFCA),3 and the risk of procedure-related complications and the rate of AF recurrence in women are higher than in men.4 AFCA is the most effective rhythm control method. It reduces heart failure mortality5 and risk of stroke6 while improving cognitive7 and renal8 functions. However, since AF is a progressive and degenerative chronic disease, it exhibits a continuous long-term recurrence even after several years of a successful AFCA followed by maintenance of sinus rhythm.9 Repeat ablation procedures are effective in restoring and maintaining sinus rhythm in the case of AF or atrial tachycardia (AT) recurrence after AFCA. However, it is not known whether there are differences between men and women with regard to the efficacy and safety of repeat AFCA procedures. The purpose of this study was to investigate whether there is sex difference in complications and recurrence rates after a second AF ablation procedure. In addition, we evaluated sex differences in the pathophysiology of AF recurrences through cardiac imaging, electroanatomical mapping and haemodynamic measurements performed during the repeat procedures.

Methods

Study population

All patients provided written informed consent for inclusion in the Yonsei AF Ablation Cohort Database (ClinicalTrials.gov Identifier: NCT02138695). From the 3282 patients who underwent a de novo AFCA procedure, the study sample included 443 patients (24.6% female, 58.5±10.3 years old, 61.5% with paroxysmal AF) who underwent a second ablation procedure due to clinical recurrence resistant to antiarrhythmic drugs (AADs) or being ineligible for AADs 3 months after the de novo AFCA (figure 1). The study exclusion criteria were (1) permanent AF refractory to electrical cardioversion; (2) AF with valvular disease grade >2; and (3) prior cardiac surgery with a concomitant AF surgery or AFCA.

Figure 1

Flow chart of patient inclusion. AAD, antiarrhythmic drug; AF, atrial fibrillation; AT, atrial tachycardia; SR, sinus rhythm.

Echocardiographic and cardiac CT evaluation

All patients underwent transthoracic echocardiography prior to de novo and repeat procedures. Left atrial (LA) dimension, left ventricular ejection fraction, peak transmitral flow velocity (E), tissue Doppler echocardiography of the peak septal mitral annular velocity (Em) and left ventricular mass index were obtained according to the American Society of Echocardiography guidelines. Three-dimensional (3D) spiral CT scans (64-channel; LightSpeed Volume CT, Brilliance 63, Philips, Amsterdam, The Netherlands) were conducted to define the pulmonary vein (PV) anatomy. The 3D spiral CT images of the LA were analysed on an imaging processing workstation (Aquarius, TeraRecon, Foster City, California, USA). For regional volumetric analyses, each LA image was subdivided according to embryological origin into venous LA, anterior LA and LA appendage.

Electroanatomical mapping and radiofrequency catheter ablation

The 3D electroanatomical mapping (NavX, St Jude Medical, Minnetonka, Minnesota, USA; or CARTO3, Johnson & Johnson, Diamond Bar, California, USA) was generated using a circumferential PV-mapping catheter through a long sheath (Schwartz Left 1, St Jude Medical). The 3D geometry of both LA and PV was generated using the electroanatomical mapping system and then merged with the 3D spiral CT images. The details of the AFCA technique and strategy for a repeat ablation have been described in our previous study.10 Systemic anticoagulation was performed with intravenous heparin to maintain an activated clotting time of 350–400 s during the procedure. An open-irrigated tip catheter (Celsius, Johnson & Johnson; NaviStar ThermoCool, Biosense Webster, Diamond Bar, California, USA; ThermoCool SF, Biosense Webster; ThermoCool SmartTouch, Biosense Webster; Coolflex, St Jude Medical, 30–35 W, 47°C; FlexAbility, St Jude Medical; ThermoCool SmartTouch, Biosense Webster; and TactiCath, St Jude Medical) was used for AFCA. We used contact force catheter in 5.2% (23 of 443; male:female=15:8) of included patients. If there were reconnections of the PV potentials or a previous linear ablation, we performed a circumferential pulmonary vein isolation (CPVI) and accomplished a bidirectional block of the CPVI, cavotricuspid isthmus and linear ablation as much as possible. After completion of the protocol-based repeat ablation, the procedure ended when no immediate recurrence of AF was observed within 10 min after cardioversion with an isoproterenol infusion (5–20 µg/min depending on beta-blocker use and a target sinus heart rate of 120 beats per minute). If further AF triggers or frequent unifocal atrial premature beats were observed under the isoproterenol effect, extra-PV foci were carefully mapped and ablated as much as possible. Although we did not conduct adenosine test to evaluate acute dormant conduction, we waited for longer than 30 min after the initial achievement of PV isolation during isoproterenol provocation test and rechecked PV isolation status before finishing the procedure.

LA pressure measurements

Haemodynamic measurements were recorded using the Prucka CardioLab electrophysiology system (General Electric Medical Systems, Milwaukee, Wisconsin). LA pressure was measured during sinus rhythm immediately after the trans-septal puncture using a 6F pigtail catheter (A&A Medical Device, Gyeonggi-do, Republic of Korea) that was inserted into the LA through a long sheath. If the initial rhythm was AF, we measured LA pressure during sinus rhythm after terminating AF using internal cardioversion (2–10 J biphasic shocks, Lifepak 12, Physio-Control, Redmond, Washington), followed by an at least 3 min waiting period to allow recovery from atrial stunning from cardioversion. We analysed LA peak pressure (v wave), LA nadir pressure (x wave), LA mean pressure and LA pulse pressure (difference between LA peak pressure and LA nadir pressure). These parameters have been defined and calculated in our previous studies.11 12

Holter monitor records and heart rate variability analysis

A GE Marquette MARS 8000 Holter analyser (General Electric Medical Systems) was used to analyse heart rate variability (HRV) based on the 24-hour Holter monitor recordings as described previously.13 Premature ventricular beats, premature atrial beats and electrical artefacts were excluded from the analysis. The HRV parameters were used as indicators of autonomic activity according to previously published guidelines.14 The mean heart rate and the following time-domain HRV parameters were analysed: mean RR interval (mean NN interval), SD of NN intervals, SD of the 5 min mean of NN intervals and root mean square of differences between successive NN intervals (rMSSD). The following parameters were calculated: very low-frequency components (<0.04 Hz), low-frequency components (LF; 0.04–0.15 Hz), high-frequency components (HF; 0.15–0.40 Hz) and LF:HF ratio. The HF and rMSSD were indicators of parasympathetic nervous activity.

Postablation management and follow-up

The patients visited the outpatient clinic at 1, 3, 6 and 12 months and every 6 months thereafter or whenever symptoms developed after AFCA. ECG was performed at every visit. A 24-hour Holter monitoring was performed at 3, 6 and 12 months and then every 6 months thereafter according to the 2012 Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society Expert Consensus Statement guidelines. Patients who suffered from symptoms of palpitations underwent Holter/event-monitor examinations to investigate the possibility of an arrhythmia recurrence. We defined AF recurrence as any episode of AT or AF lasting for 30 s or more. Any ECG documentation of an AF recurrence after a 3-month blanking period was classified as a clinical recurrence.

Statistical analysis

Continuous variables are expressed as mean±SD. Categorical variables are reported as count (percentage). We compared the clinical characteristics, AFCA procedure-related characteristics, mapping findings and repeat ablation outcomes between female and male patients using Student’s t-test for continuous variables and χ2 or Fisher’s exact test for categorical variables.

We investigated the changes in LA voltage, LA pressure and HRV between de novo and redo ablation procedures in overall, male and female patients using a paired t-test. We performed propensity score matching without a replacement and with a calliper of 0.1 at a female to male ratio of 1:2 based on age and AF type. In this propensity score-matched population, we compared the presence of extra-PV triggers, changes in LA voltage, LA pressure and HRV, and clinical rhythm outcomes between the female and male groups. We performed multivariate Cox regression analysis using the variables which had a p value <0.05 in the univariate Cox regression analysis and age. We used backward elimination stepwise method in the multivariate Cox regression analysis. Variables with p values >0.1 in the multivariable model were individually removed in a backward stepwise method. We confirmed the proportional hazard assumption after Schoenfeld test. The time-dependent, AF-free survival rates were compared by Kaplan-Meier analyses. A p value <0.05 was considered statistically significant. All statistical analyses were performed using SPSS (Statistical Package for Social Sciences, V.23.0) software for Windows.

Results

Patient characteristics

Table 1 summarises the patients’ characteristics. Among the 443 patients who underwent a second AFCA, 109 were women and 334 were men. The mean age was 58.5±10.3 years, and 61.5% of the cases had the paroxysmal type at the time of the repeat procedure. The mean CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, sex category (female)) score was 1.6±1.4. The time from de novo procedure to repeat procedure was 22 (IQR, 11–52) months. In female patients, the proportion of heart failure was higher (p<0.001), related to a higher E/Em (p<0.001) and the LA volume index (p<0.001), but mean LA voltage (p=0.002) and pericardial fat volume (p<0.001) were significantly lower than in men.

Table 1

Baseline clinical characteristics

Lower PV reconnections and greater extra-PV triggers in women

Table 2 summarises the mapping and ablation findings of the repeat procedures. During the repeat mapping procedure, 41.3% of women had no reconnected PV potentials, which was higher than among men (25.1%, p=0.001), but women had greater proportions of extra-PV triggers in response to an isoproterenol provocation (27.5% vs 17.0%, p=0.026). The locations of the extra-PV triggers are summarised in table 3. During the second ablation procedure, a posterior box isolation was more commonly achieved in women than in men (p=0.031). There was no significant sex difference related to the overall procedure (p=0.791) or in the rate of major complications (p=0.695).

Table 2

Procedure-related characteristics

Table 3

Locations of extra-PV triggers at repeat ablations (after propensity score matching)

Stiff LA was more common in women

Although the mean LA voltage was significantly lower in women than in men during the repeat procedure (p=0.038), there was no significant change in the mean LA voltage between the de novo and repeat procedures (table 4). The LA peak pressure was elevated during the repeat procedures in women (p<0.001). LA pulse pressure (p<0.001 for both women and men) was elevated during the repeat procedures in male and female patients. The proportion of patients who had an elevated LA pulse pressure, which reflected LA stiffness, was significantly higher in women than in men (79.7% vs 63.7%, p=0.019; table 4). In the third month post procedure, the HRV parameters, including HF (p=0.010) and rMSSD (p=0.006), which reflect parasympathetic nervous activity, were consistently higher in women than in men (table 4).

Table 4

Changes in LA voltage, pressure and heart rate variabilities (after propensity score matching)

Worse rhythm outcomes in women

Table 5 summarises the clinical and rhythm outcomes of the repeat procedures. AADs were maintained at 29.1% at discharge and at 39.7% 3 months after the repeat procedures without any sex difference. During a median follow-up of 31 (8–60) months, the rate of clinical recurrence was significantly higher in women after both the de novo (log-rank p=0.039, AAD-free log-rank p<0.001; figure 2A,B) and repeat (log-rank p=0.006, AAD-free log-rank p=0.093; figure 2C,D) procedures. However, there was no sex difference in the proportion of recurrences as AT (p=0.373) or cardioversion (p=0.432) during the follow-up period (table 5). In the multivariate Cox regression analyses, female sex (HR 1.51, 95% CI 1.06 to 2.15, p=0.023), non-paroxysmal AF (HR 1.78, 95% CI 1.30 to 2.34, p<0.010) and extra-PV triggers (HR 1.88, 95% CI 1.28 to 2.75, p=0.001) were independently associated with clinical recurrences after repeat procedures (table 6).

Figure 2

Kaplan-Meier analyses of AF-free survival after de novo ablation procedures (A and B) and second AF ablation procedures (C and D). AAD, antiarrhythmic drug; AF, atrial fibrillation.

Table 5

Clinical rhythm outcomes (after propensity score matching)

Table 6

Cox regression analysis for clinical recurrences

Discussion

Main findings

In this retrospective cohort study of 443 patients who underwent a second AFCA, there was no sex difference in the rate of procedure-related complications, but the rate of AF recurrence after the repeat procedure was significantly higher in women than in men. During the repeat AFCA procedure, the rate of PV reconnection was lower and extra-PV triggers and LA pressure elevation were more common in women than in men, which may have resulted in a poor rhythm outcome.

Sex differences in AF

AF is a common arrhythmic disease with a higher incidence and prevalence in men, but comorbidities, risk of stroke and mortality are significantly higher in women.2 15 A haemodynamic factor might be one of the significant pathophysiological differences between men and women among patients with AF. In general, left ventricular (LV) diastolic dysfunction, including heart failure with a preserved ejection fraction, is more commonly observed in women than in men,16 17 because central aortic stiffness, which increases with age, readily transitions into load-dependent LV diastolic dysfunction in women.18 Therefore, AF perpetuates LA electroanatomical remodelling in relation to the LV diastolic dysfunction, which results in atrial myopathy and reduced LA appendage function and eventually increases the risk of stroke.17 19 Yu et al 20 demonstrated that the mechanistic linkage among an impaired LV diastolic function, LA structural changes and LA appendage contractile dysfunction is more pronounced in women than in men among patients with AF.

Sex differences in the effectiveness of AFCA

AFCA is the most effective rhythm control treatment, but the recurrence rate is higher in women, especially in relatively young women under the age of 60, as compared with men.21 The later the recurrence period after a de novo ablation, the more often there are no PV reconnections,22 and the rhythm outcomes of a repeat ablation are poorer in patients without PV reconnections.10 This suggests that the extra-PV foci and accompanying AF progression play important roles in the mechanism of AF recurrence in patients without PV reconnections. In this study, there were fewer PV reconnections and more extra-PV foci in the repeat mapping in women as compared with men, and the resulting rhythm outcome after the repeat ablation was significantly worse in women than in men.

The degree of atrial electroanatomical remodelling and the presence of extra-PV foci are important predictive indicators of AF recurrence.23 24 Women are disproportionately more vulnerable to the series of inflammatory processes involving oxidative stress, myofibroblast activation and calcium overload,25 which are associated with atrial remodelling.26 This explanation is supported by the results of this study in that the LA voltage was lower, extra-PV foci were more frequent and the chance of a stiff LA after the do novo ablation was higher in female patients than in male patients. Another important mechanism of AF recurrence is the contribution of the autonomic nervous activity.27 Yu et al 21 reported that a decrease in the parasympathetic nervous activity after AFCA was smaller in women than in men and was associated with AF recurrence. In this study, the rhythm outcomes were poorer in women, even after the repeat ablation procedures with consistent mechanisms.

Sex differences in the safety of AFCA

With the ageing of the population structure, the number of AFCA procedures will continue to increase, and the rate of procedure-related complications has been reported to range from 3% to 6.3%.28 Although there was no statistical difference between male and female patients in the rate of complications in this study, it has been reported that female patients generally have relatively more adverse outcomes than male patients after AFCA.29 30 The greater risk of a haemopericardium and the lower PV reconnection rate in women suggest that these outcomes might be related to sex differences in LA wall thickness (data not shown).

Limitations

Several potential limitations of this study should be considered. First, this study was a single-centre retrospective study with a relatively small number of patients. Although the indications for patient selection and the protocols for mapping and repeat ablation procedures were strictly controlled by the investigators, the results of this study cannot be generalised. Second, a regular rhythm follow-up schedule based on the guidelines was followed, but the exact AF burden could not be assessed by Holter monitoring alone. Third, there were limitations to the amount of data for the LA endocardial voltage (41.3%), LA pressure during sinus rhythm (59.6%) and HRV (35%) that were available for both the de novo and repeat ablation procedures. The missing variables in this study are reported in table 1, with a total number of each variable used in the analysis. Fourth, although we waited for 3 min before measuring the LA pressure to allow recovery from atrial stunning from cardioversion, recovery of atrial stunning has been shown to be heavily dependent on the duration of AF. A future multicentre, prospective, observational study with a larger number of patients is warranted.

Conclusions

During repeat AFCA procedures, the rate of PV reconnection was lower and the existence of extra-PV triggers and an LA pressure elevation were more significant in women than in men and resulted in poor rhythm outcomes.

Key messages

What is already known on this subject?

  • The rate of atrial fibrillation (AF) recurrence in women is higher than in men after AF catheter ablation, but the reasons are unclear.

What might this study add?

  • During repeat AF ablation procedures, the rate of pulmonary vein (PV) reconnection was lower in women than in men (58.7% vs 74.9%, p=0.001), and the existence of extra-PV triggers (27.5% vs 17.0%, p=0.026) and a left atrial pressure elevation (79.7% vs 63.7%, p=0.019) were more common, which resulted in poor rhythm outcomes in women.

How might this impact on clinical practice?

  • Women are disproportionately more vulnerable to atrial remodelling, and extra-PV foci and the accompanying AF progression play important roles in the mechanism of AF recurrence without PV reconnections.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Data, analytic methods and study materials are available upon reasonable request to other researchers who want to reproduce the results or replicate the procedure.

Ethics statements

Patient consent for publication

Ethics approval

This study protocol adhered to the principles of the Declaration of Helsinki and was approved by the Institutional Review Board at the Yonsei University Health System.

Acknowledgments

The authors thank Mr John Martin for linguistic assistance.

References

Footnotes

  • Contributors H-NP designed the study, analysed and interpreted the data, drafted the manuscript, and did the final approval of the manuscript submitted. J-WP analysed and interpreted the data. S-YY analysed the data and prepared the tables and figures. MK, HTY, T-HK and J-SU contributed to acquiring patients’ clinical data. BJ and M-H revised the manuscript critically for important intellectual content.

  • Funding This work was supported by a grant (HI19C0114) from the Korea Health 21 R&D Project, Ministry of Health and Welfare, and by a grant (NRF-2020R1A2B01001695) from the Basic Science Research Program run by the National Research Foundation of Korea (NRF).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.