Left atrial appendage size is a marker of atrial fibrillation recurrence after radiofrequency catheter ablation in patients with persistent atrial fibrillation

Abstract Introduction There are no consistently confirmed predictors of atrial fibrillation (AF) recurrence after catheter ablation. Therefore, we aimed to study whether left atrial appendage volume (LAAV) and function influence the long‐term recurrence of AF after catheter ablation, depending on AF type. Methods AF patients who underwent point‐by‐point radiofrequency catheter ablation after cardiac computed tomography (CT) were included in this analysis. LAAV and LAA orifice area were measured by CT. Uni‐ and multivariable Cox proportional hazard regression models were performed to determine the predictors of AF recurrence. Results In total, 561 AF patients (61.9 ± 10.2 years, 34.9% females) were included in the study. Recurrence of AF was detected in 40.8% of the cases (34.6% in patients with paroxysmal and 53.5% in those with persistent AF) with a median recurrence‐free time of 22.7 (9.3–43.1) months. Patients with persistent AF had significantly higher body surface area‐indexed LAV, LAAV, and LAA orifice area and lower LAA flow velocity, than those with paroxysmal AF. After adjustment left ventricular ejection fraction (LVEF) <50% (HR = 2.17; 95% CI = 1.38–3.43; p < .001) and LAAV (HR = 1.06; 95% CI = 1.01–1.12; p = .029) were independently associated with AF recurrence in persistent AF, while no independent predictors could be identified in paroxysmal AF. Conclusion The current study demonstrates that beyond left ventricular systolic dysfunction, LAA enlargement is associated with higher rate of AF recurrence after catheter ablation in persistent AF, but not in patients with paroxysmal AF.


Conclusion:
The current study demonstrates that beyond left ventricular systolic dysfunction, LAA enlargement is associated with higher rate of AF recurrence after catheter ablation in persistent AF, but not in patients with paroxysmal AF.

K E Y W O R D S
atrial fibrillation, echocardiography, heart atria, recurrence, transesophageal, transthoracal, tomography, X-ray

| INTRODUCTION
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. 1 It can lead to several health problems, such as heart failure, embolic events, and impaired quality of life. Moreover, it is associated with higher mortality rate. [2][3][4] In case of drug-resistant symptomatic AF, catheter ablation proved to be an effective solution for rhythm control. 5 However, depending on the ablation strategy and the type of AF, success rates of catheter ablation after 1 year vary considerably from 60% to 90%. [5][6][7] Appropriate patient selection for catheter ablation is essential as neither AF recurrence nor procedural complication rates are negligible. 8 However, there are no consistently confirmed predictors of AF recurrence following catheter ablation in the literature. [9][10][11][12][13][14][15][16][17][18] It has been suggested that left atrial appendage (LAA) volume and function may be associated with the recurrence of AF/tachycardia in patients undergoing repeated ablation, the exact role of the LAA in the prediction of AF recurrence has not yet been resolved. 19 The anatomy, including LAA volume, morphology and LAA orifice area can be accurately described using cardiac computed tomography (CT), and LAA function can be assessed by measuring LAA flow velocity using transesophageal echocardiography (TEE).
We aimed to study the role of LAA volume (LAAV), and function in the success of catheter ablation by type of AF.

| Cardiac CT imaging
CT examinations were performed with a 256-slice scanner (Brilliance iCT 256, Philips Healthcare, Best, The Netherlands) with prospective ECG-triggered axial acquisition mode. 100-120 kV with 200-300 mAs tube current was used depending on patient anthropometrics.
Image acquisition was performed with 128 Â 0.625 mm detector collimation, and 270 ms gantry rotation time. For heart rate control 50-100 mg metoprolol was given orally and 5-20 mg intravenously, if necessary. In patients with a heart rate of <80/min, mid-diastolic triggering was applied with 3%-5% padding (73%-83% of the R-R interval), and in those with ≥80/min, systolic triggering was chosen (35%-45% of the R-R interval) regardless of the presence of AF at the ECG during CT examination. In total 85-95 ml contrast material (Iomeron 400, Bracco Ltd., Milan, Italy) was injected with a flow rate of 4.5-5.5 ml/s via antecubital vein access using a four-phasic injection protocol. 20 Bolus tracking in the LA was used to obtain proper scan timing. All patients received 0.

| Catheter ablation procedure
The indications for AF ablation procedures were in accordance with the current guidelines. 1,21 Paroxysmal AF was defined as self-terminating AF, in most cases within 48 hours. Some AF paroxysms continued up to 7 days. 21 Persistent AF was defined as AF that lasts longer than 7 days. 21 Conscious sedation was carried out in all cases with intravenous fentanyl, midazolam, and propofol. Basic vital parameters of the patients were monitored in all cases with non-invasive blood pressure measurements every 10 min and continuous pulse oximetry. Femoral venous access was used for all procedures. Transseptal puncture was performed routinely with fluoroscopy guidance and pressure monitoring, while intracardiac echocardiography was also utilized in difficult cases. All ablations were performed with the support of an electroanatomical mapping system (either CARTO, Biosense Webster, Inc., Diamond Bar, CA, USA; or ENSITE, St. Jude Medical, Inc., MN, USA), and the LA fast anatomical map was fused with the cardiac CT images to guide ablation (temperature-controlled mode, 43 C, 25-35 W, irrigated 4 mm tip catheter) in the majority of patients. Pulmonary vein isolation was performed in each patient. Moreover, in patients with long-standing persistent AF, additional ablation lines were drawn at the discretion of the operating physician. All patients without complications were discharged the day after the procedure.

| Follow-up and definition of AF recurrence
After discharge, outpatient clinical follow-up visits were scheduled at 3, 6, and 12 months after the procedure and at least once yearly thereafter. The follow-up visits included clinical assessment of the patient and 24-hour Holter ECG monitoring. Follow-up data were registered in the structured reporting platform (Axis, Neumann Medical Ltd, Budapest, Hungary). Recurrence of AF was defined as the occurrence of atrial tachyarrhythmia that lasted for more than 30 s with or without symptoms. 1,21 AF recurrences during the first 90 days after catheter ablation were not included in order to exclude AF during this vulnerable "blanking period", which might be only a temporary phenomenon due to the inflammation, maturation and healing of the ablated lesions. 22 Correlation among LA and LAA parameters are reported in Figure S1. Detailed data on the clinical and imaging parameters by AF type can be seen in Table 2 and Figure 1.

| Predictors of AF recurrence
Significantly higher iLAV and LAAV values were measured in patients with persistent AF recurrences, and larger LAA orifice area values were measured both in paroxysmal and persistent recurrences, as reported in  Table 3. Kaplan-Meier curves of AF recurrence-free survival in persistent AF stratified by LVEF and LAAV can be seen in Figure 2, Figures S2 and S3.

| DISCUSSION
We demonstrated that beyond impaired LVEF, a larger LAAV is an independent predictor of AF recurrence after catheter ablation in AF is a complex disease with incompletely understood mechanisms.
Although significant progress has been made in the last two decades, the efficacy of ablation therapy remains suboptimal, particularly in persistent AF. One-year success rate of catheter ablation varies between 60% and 90%. [5][6][7] Previous studies have shown that the majority of AF recurrence occurred in the first 2 years after catheter ablation. 24 34 In line with these findings, our results also suggest that LAAV may be a surrogate of increased LAA arrhythmogenicity. LAA has a complex anatomy and LAA enlargement might result in longer activation pathways and development of re-entry through interstitial fibrosis. 35 Previous studies have shown that LAA remodeling (dilatation, stretching, reduction of pectinate muscles, endocardial fibroelastosis) can occur in chronic AF. 36,37 This might explain that larger LAAV was associated with persistent, but not with paroxysmal AF in our study.
The current study has several limitations. First, it was a singlecenter, retrospective study, therefore the results need further validation in prospective, multicenter studies. Second, even if patients were closely followed-up with regular clinical visits, ECG and Holter monitoring, asymptomatic AF episodes might have happened between two visits. Moreover, ablation strategy was not uniform in all subjects, as additional ablations were permitted beyond PVI if operator decided to draw additional lines. However, our analysis includes a large number of patients with a long follow-up period. In addition, we included patients only who underwent point-by-point radiofrequency catheter ablation, which ensures homogenous cohort in terms of procedure technique. Furthermore, in order to exclude AF recurrences during the "blanking period" when arrhythmias might be caused by postprocedural inflammation and maturation, cases during the first 90 days were not included in our analysis. Another strength of our study is that all cardiac CT was performed by a 256-slice machine, which allows more precise imaging and measurement of LA and LAA volumes.

| CONCLUSION
Despite advances in catheter ablation techniques, AF recurrence rate is relatively high. The current study demonstrates that beyond left ventricular systolic dysfunction, LAA enlargement is an independent predictor of AF recurrence after catheter ablation in persistent AF. Our results suggest that preprocedural assessment of LVEF and LAAV might contribute to optimal patient selection and aid to improve long-term results of ablation procedures in patients with persistent AF.