Left atrium remodeling predicts late recurrence of paroxysmal atrial fibrillation after second generation cryoballoon ablation

We retrospectively included 209 patients having undergone CBA for paroxysmal AF in our center from January 2014 to February 2016.

Baseline demographic characteristics can be found in Table 1. CHA₂DS₂-VASc score was calculated according to European Society of Cardiology Guidelines [1].

The study was approved by the local Ethical Committee and was carried out in accordance with the ethical principles for medical research involving human subjects established by Helsinki’s Declaration, protecting the privacy of all participants, as well as the confidentiality of their personal information. All patients provided written informed consents.

A comprehensive transthoracic echocardiography (TTE) (using GE Vingmed Ultrasound, Vivid E9, Horten, Norway; Phillips Epiq, Philips, Andover, Massachusetts) was performed in all patients, according to the recommendations [10, 11]. Standard parasternal long and short axis views and apical two-, three - and four - chamber views were available in all patients. Left ventricular (LV) dimensions were measured using M – Mode in the parasternal long axis view. LAD was measured using anatomical M-mode and two – dimensional assessment (2D) in the parasternal long axis view. LA maximum (LAmax) and minimum (LAmin) volumes were measured in two - and four chamber views, using the biplane area-length method (Fig. 1). LA volumes were indexed based on the patient’s body surface area. Left atrium superior - inferior diameter was measured in apical two - and four chamber views (Fig. 2). Doppler mitral inflow peak early diastolic (E), peak atrial systolic velocities (A) and deceleration time were measured. Tissue Doppler imaging at the level of the mitral annulus was used to measure peak early diastolic septal and lateral e’, as well as peak late diastolic a’, corresponding to the P-wave on the electrocardiogram (ECG) [10, 12].

To determine the reproducibility of the LAD, LA superior – inferior diameter, LAmax and LAmin, the measurements were repeated in 20 randomly selected patients by an additional investigator and by the same primary investigator 1 week later. During the repeated analysis, the investigators were blinded to the results of all previous measurements.

The antiarrhythmic drugs (AADs) were discontinued at least 3 days before the procedure, except for amiodarone, which was stopped one month before.

Our standard ablation procedure has been previously reported in detail [13]. Briefly, after obtaining LA access, through a steerable 15 Fr sheath (FlexCath Advance®, Medtronic©), an inner lumen mapping catheter (ILMC) (Achieve®, Medtronic©) was advanced in each pulmonary vein (PV) ostium and baseline electrical information was gathered. Optimal vessel occlusion was considered as achieved upon selective contrast injection showing total contrast retention with no backflow into the atrium. Once occlusion was documented, cryothermal energy was started for at least 180 s. Usually, the PVs were treated as follows: first, the left superior PV (LSPV), then the left inferior (LIPV), right inferior (RIPV) and right superior (RSPV). PV activity was recorded with the ILMC at a proximal site within the ostium prior to ablation in each vein. If PV potentials (PVPs) were visible during energy delivery, time to isolation was recorded as the time from the start of the cryoenergy application until the PVPs completely disappeared or were dissociated from LA activity. In cases of phrenic nerve palsy (PNP), recovery of diaphragmatic contraction was carefully monitored for 30 min. Further additional cryoenergy applications were not applied if the veins were isolated after the initial freeze. If needed, pacing from the distal and/or proximal coronary sinus was performed to recognise far field atrial signals from PVPs recorded on the mapping catheter. During the whole procedure, activated clotting time was maintained > 250 s. In order to avoid phrenic nerve palsy, diaphragmatic stimulation was achieved by pacing the phrenic nerve during septal pulmonary veins ablations.

Patients were discharged the day after ablation if the clinical status was stable. Following the procedure, all the patients were continuously monitored with ECG telemetry for at least 18 h. Oral anticoagulation was not discontinued for the ablation and continued for at least 2 months following the CHA₂DS₂ - VAsc score. During the blanking period (BP), AADs were continued. The decision to continue AADs after the BP or to perform a repeat procedure was taken if a first episode of recurrence of AF occurred.

All the included patients underwent physical examination and a 24 h Holter recording at 1, 3, 6 and 12 months after the ablation. Additional Holter monitoring was performed if arrhythmic symptoms occurred. All documented AF episodes > 30 s were considered as a recurrence. A BP of 3 months was considered for the study.

Baseline clinical and demographic characteristics of the study population are listed in Table 1. There was a significant difference between the groups with and without recurrence for patients who presented early AF recurrence.

Echocardiographic characteristics are presented in Table 2. In brief, there was a significant difference in patients with and without recurrence respectively for LV end-diastolic diameter (50.3 ± 7.9 mm vs. 47.2 ± 6.5 mm, p = 0.013), LV mass index (83.7 ± 28.4 g/m² vs. 76.6 ± 26.3 g/m², p = 0.045), LAD (42.2 ± 7.2 mm vs. 39 ± 6.1 mm, p = 0.013), LAmax (67.3 ± 27.8 mL vs. 57.7 ± 21.2 mL, p = 0.036), LAmin (36.7 ± 20.1 mL vs. 27.5 ± 14.9 mL, p = 0.004) and LAmin indexed (18.1 ± 9.3 mL/m² vs. 14.1 ± 7.4 mL/m², p = 0.007).

All the patients underwent the procedure with the large 28-mm CBA. At the beginning of the procedure, 203 (97.1%) patients were in sinus rhythm. The mean total procedure and fluoroscopy time were 66.9 ± 20.2 min, respectively 13.8 ± 7.5 min. The mean number of freeze-thaw cycles was 1.2 ± 0.4 in the LSPV, 1.1 ± 0.3 in the LIPV, 1.19 ± 0.44 in the RSPV, 1.2 ± 0.5 in the RIPV. The mean minimal temperatures obtained were − 48.7 ± 8.6 °C in LSPV, − 48.7 ± 8.6 in LIPV, − 49.2 ± 10.8 in RSPV, − 46 ± 14.6 in RIPV. There were no significant differences regarding the procedural data between the two groups. Procedural data can be found in Table 3.

Fig. 3 illustrates that using only the LAD, with an adjusted cut-off value of 41 mm, led missing up to 30.2% of AF recurrences. In the patients with recurrence without LAD dilation, a significant number of patients had longitudinal LA remodeling (increased superior – inferior LA diameter, with an adjusted cut-off value of 41 mm).

Multivariate regression analysis showed that LAD, LAmin and early AF recurrence were independent predictors of AF recurrence after the BP, as illustrated in Table 4.

ROC analysis revealed that for a cut-off value of 23.69 ml for LAmin it was associated with a high sensitivity for predicting AF recurrence after the BP (79.5% sensitivity, 46% specificity). For the above mentioned adjusted cut-off values, LAmin had a high negative predictive values for AF recurrences 87.3% .

In contrast, for LAD, sensitivity and specificity were 56.3% and 66%, respectively, with a lower negative predictive value of 73% compared to LAmin.

Intraobserver variability was excellent for all the parameters. For LAD the ICC was 0.972, for LA superior – inferior diameter ICC = 0.95, for LAmax ICC = 0.964 and for LAmin ICC = 0.940. Interobserver reliability was good for LAD (ICC = 0.906), LAmax (ICC = 0.907) and LAmin (0.860) and excellent for LA superior – inferior diameter (ICC = 0.96).

This is a single center retrospective study, therefore results may not be generalized. Larger prospective clinical studies are warranted to confirm our findings. Moreover, the present study addressed the prognostic value of LA anatomy only in paroxysmal AF and cannot be extrapolated to a persistent AF population undergoing CBA.

As mentioned earlier, it is widely accepted that anatomical remodeling is associated with recurrence of AF after ablation [4, 6, 9, 16, 21, 22]. 2D echocardiography can provide useful information for the detection of patients at risk to develop recurrences of AF, but LA volumes are still based on only two orthogonal planes and related to geometrical assumptions. Our results suggest that LA longitudinal remodeling could play an additional role in the prediction of AF recurrences, as the expansion of the LA can be asymmetrical. Therefore, advanced imaging techniques such as three – dimensional (3D) echocardiography can overcome these limitations and provide more accurate and reproducible LA measurements [23]. Moreover, several studies showed that LA strain could predict recurrence of AF after catheter ablation. Therefore, strain imaging may bring additional information regarding the more subtle structural and functional left atrium remodeling in such patients and could be used for the follow-up assessment of possible reverse atrial remodeling [24‐26].