Clinical significance of early atrial arrhythmia type and timing after single ring isolation of the pulmonary veins

Abstract

Aims

Early atrial arrhythmia following atrial fibrillation (AF) ablation is associated with higher recurrence rates. Few studies explore the impact of early AF (EAF) and atrial tachycardia (EAT) on long-term outcomes. Furthermore, EAF/EAT have not been characterized after wide pulmonary vein isolation. We aimed to characterize EAF and EAT and its impact on late AF (LAF) and AT (LAT) after single ring isolation (SRI).

Methods and results

We recruited 119 (females 21, age 58 ± 10 years) consecutive patients with AF (paroxysmal 76, persistent 43) undergoing SRI. Early atrial fibrillation/ early atrial tachycardia was defined as AF/AT within 3 months post-procedure (blanking period). Patients were followed for median 2.8[2.2–4] years. Early atrial fibrillation occurred in 28% (n = 33) and EAT in 25% (n = 30). At follow-up, 25% (n = 30) had LAF and 28% (n = 33) had LAT. Patients with EAF and EAT had higher rates of LAF (48 vs. 16%, P<0.0001) and LAT (60 vs. 16%, P < 0.0001), respectively. Independent predictors of LAF were EAF (3.53(1.72–7.29) P = 0.001); and of LAT were EAT (5.62(2.88–10.95) P < 0.0001) and procedure time (1.38/ h(1.07–1.78) P = 0.04). Importantly, EAF did not predict LAT and EAT did not predict LAF. Early atrial fibrillation late in the blanking period was associated with higher rates of LAF (73% for month 3 vs. 25% for Months 1–2, P = 0.004). However, EAT timing did not predict LAT.

Conclusion

Early atrial fibrillation and EAT are predictive of LAF and LAT, respectively. Early atrial fibrillation late in the blanking period has greater predictive significance for LAF. This timing is not relevant for LAT. Early arrhythmia type and timing have important prognostic significance following SRI.

Clinical Trial Registration

http://www.anzctr.org.au;ACTRN12606000467538.

Introduction

Current HRS/EHRA/ECAS guidelines for catheter ablation of atrial fibrillation (AF) advocate a blanking period of 2 to 3 months following the procedure.¹ Oral et al.² demonstrated that up to 35% patients had early recurrence of AF (EAF) following ablation, and that EAF was associated with lower long-term success. However, up to 30% patients with EAF have no further symptomatic AF during long-term follow-up.¹ Weaker associations have also been shown in relation to early recurrence of atrial tachycardia (EAT) following AF ablation.³ However, it is important to realize that previous studies have either utilized an endpoint of recurrent AF or a common endpoint of recurrent AF and AT.^4–9 The value of EAF and EAT to each predict recurrent AF vs. AT has not been examined in detail. Furthermore, the mechanisms of AF and AT following ablation are different and the impact of EAF and EAT on long-term outcomes warrants evaluation.

The impact of early arrhythmias on long-term outcomes following AF ablation has only been evaluated in relation to a limited number of lesion sets.^2,7,9 Lim et al.¹⁰ previously demonstrated that single ring isolation (SRI) results in fewer AF and similar AT recurrence rates in the long term compared with wide antral isolation. However, the impact of wide isolation with a single ring of lesions on early and late recurrence (AF and AT) has not been reported.

The aim of this study was to characterize the impact of EAF and EAT in a series of patients having SRI for AF.

Methods

We recruited 119 patients with highly symptomatic AF referred for a first catheter ablation procedure to Westmead Hospital, Sydney, Australia. This study was approved by the Sydney West Area Health Service Human Research Ethics Committee and complies with the Declaration of Helsinki. All patients provided informed consent.

Ablation strategy

All patients underwent an SRI strategy of the pulmonary veins. The technique used has been described in detail previously.¹⁰ In addition to SRI, patients were randomized in a 1 : 1 ratio to have mitral isthmus line (MIL) ablation. We have previously described the results of MIL ablation in this patient cohort.¹⁰

In brief, all patients underwent a pre-procedural trans-oesophageal echocardiogram to exclude left atrial thrombus and to visualize the inter-atrial septum. Following trans-septal puncture, a lasso catheter (Biosense Webster) and an irrigated tip ablation catheter (Biosense Webster) within a steerable sheath (Agilis, St Jude Medical) were advanced to the left atrium. An electro anatomical map was generated using a three-dimensional navigation system (Carto/NavX) and merged with a pre-procedurally acquired cardiac computed tomography. The ablation catheter was used to apply a single ring of lesions encircling all PV's. Power up to 30 W was applied on the left atrial posterior wall and up to 40 W elsewhere in the left atrium.

Half of the patients underwent MIL ablation. Conduction block was confirmed by delayed conduction across the line during standard pacing manoeuvers in sinus rhythm. In addition, regions of complex fractionated atrial electrograms (CFAE) were targeted in patients with persistent AF in whom AF continued despite electrical isolation of the pulmonary veins. Complex fractionated atrial electrograms ablation was performed mostly on the septum and roof within the left atrium. Class I and III anti-arrhythmic drugs were stopped before discharge.

Follow-up

Patients were followed with regular clinic visits pre-procedurally, and following the procedure at 3, 6, 9, 12, 18 and 24 months. Seven-day Holter monitoring was performed at 6, 12 and 24 months following the procedure. Medical professionals involved in patient care remote from our institution were also contacted to obtain clinical information to ensure comprehensive follow-up.

Definitions of early and late recurrence

Recurrent atrial arrhythmia (AF and atrial tachycardia) was defined as an episode of sustained AF or AT >30 s duration. We defined early recurrence of AF (EAF) or AT (EAT) as occurring <3 months following ablation (usually considered a blanking period as per the HRS/EHRA/ECAS AF ablation guidelines). Patients with AF/AT within the first 3 months of ablation were electrically or chemically cardioverted to sinus rhythm. Patients who had both EAF and EAT were included in both groups for analysis.

Atrial tachycardia was defined as a regular, organized supraventricular rhythm at a constant atrial rate of ≥100 beats/min. All early and late recurrences were classified as AF or AT, depending on the morphology and regularity of rhythm.^1,11 The clinical endpoint was late AF (LAF) or late AT (LAT) defined as AF/AT >3 months after ablation. All recurrences refer to single procedure recurrence rates.

Statistical analysis

Continuous variables are expressed as mean ± SD and were compared using the Student's t test. Categorical variables were compared by Fisher's exact test or χ² test as appropriate. A Kaplan–Meier analysis was used to determine the probability of freedom from recurrent arrhythmia during follow-up. The log rank test was used to compare survival distributions between groups. A general linear model with repeated measures was utilized to determine univariate and multivariate predictors of EAT and LAT. Persistent AF and CFAE ablation were highly correlated variables. Persistent AF was included in the model because it was considered a more relevant clinical characteristic. Cox regression analysis with inclusion of all univariable predictors of recurrence with P < 0.1 was performed to determine independent clinical predictors of LAF and LAT. A value of P < 0.05 was considered significant.

Results

Early atrial fibrillation and early atrial tachycardia

One hundred and nineteen consecutive patients having SRI were recruited. Sixty (50%) patients had MIL ablation, of which 36 (60%) patients had conduction block across the MIL. Twenty-one (18%) patients had CFAE ablation. Early atrial fibrillation occurred in 33 (28%) patients and EAT in 30 (25%) patients. Of these, 8 (7%) patients had both EAF and EAT. (Figure 1) Characteristics were similar among patients with and without MIL ablation.

Baseline characteristics of patients are described in Table 1. There were no demographic, clinical or procedural differences between patients with EAF and EAT. Patients with early arrhythmia (EAF and EAT) had more persistent AF (38 vs. 28%, P = 0.04). Patients with early arrhythmia more commonly had CFAE ablation (26 vs. 11%, P < 0.05), had longer procedure times (325 ± 80 vs. 291 ± 66 min, P = 0.017), received more radiofrequency ablation (84 ± 26 vs. 72 ± 19 min, P = 0.006) and had more intraprocedural AF (69 vs. 45%, P = 0.01). Atrial tachycardia during the procedure was not significantly different between the groups. After multivariate analysis, independent predictors of early arrhythmia were procedure time (1.26/h (1.01–1.56), P = 0.04) and intraprocedural AF (2.06 compared with no procedural AF (1.08–3.93), P = 0.03). Persistent AF was a univariate but not a multivariate predictor of early arrhythmia (see Table 2).

Late atrial fibrillation/atrial tachycardia recurrences

After a minimum follow-up of 2 years [median 2.8 years (inter-quartile range 2.2–4)], LAF occurred in 30 (25%) patients and LAT in 33 (28%) patients. Four (3%) patients had both LAF and LAT. The combined endpoint of late atrial arrhythmia (LAF and LAT) was higher in patients with early arrhythmia compared with patients without (69 vs. 31%, P < 0.0001) (Figure 2A).

Twenty-seven (45%) patients with MIL compared with 28 (47%) patients without MIL had late atrial arrhythmia recurrence (P = 0.85).

Recurrence rates of LAF and LAT were assessed in patients with EAF, EAT, and without early arrhythmia. Forty-eight percent (16 out of 33) of patients with EAF had LAF, compared with 10% (3 out of 30) of patients with EAT and 17% (11 out of 64) of patients without early arrhythmia. Rates of LAF were significantly higher among patients with EAF vs. those with EAT (P = 0.001) or no early arrhythmia (P = 0.001). LAF rates were similar in patients with EAT and no early arrhythmia (P = 0.49) (Figure 2B). A similar pattern was observed in the case of atrial tachycardia. Sixty-three percent (19 out of 30) of patients with EAT had LAT, compared with 15% (5 out of 33) of patients with EAF and 14% (9 out of 64) of patients without early arrhythmia. Rates of LAT were significantly higher among patients with EAT vs. those with EAF (P = 0.002) or no early arrhythmia (P < 0.0001). LAT rates were similar among patients with EAF and no early arrhythmia (P = 0.26) (Figure 2C).

In cases of procedural AT, the tachycardia was mapped to the point of earliest activation and ablated. In most cases AT was secondary to re-entry enabled by ring gaps. The proportion of patients with procedural AT was similar in patients with and without LAT (20 (61%) with LAT and 45 (52%) without LAT, P = 0.54).

Univariate predictors of LAF were EAF and persistent AF. After multivariate analysis, the only independent predictor of LAF was EAF. In the case of LAT, EAT and procedure time, were both univariate and multivariate predictors of recurrence. Notably, having EAF did not predict LAT, nor did having EAT predict LAF in univariable or multivariable analysis (See Table 3).

Relationship between early arrhythmia timing and late atrial fibrillation or late atrial tachycardia

The greatest proportion of early arrhythmia occurred in the first 2 months of the blanking period. Seventy-six percent of EAF (n = 25) and 83% of EAT (n = 25) occurred in the first 2 months of the blanking period.

The time of first occurrence of EAF and EAT in the blanking period was correlated with LAF and LAT, respectively (Figure 3A and B). Twenty-five percent of patients with EAF in the first 2 months of the blanking period had LAF, compared with 73% of patients with EAF in the third month (P = 0.004). However, there was no association between LAT and month of EAT (43% in the first 2 months vs. 36% in the third month, P = 0.90).

Discussion

In the present study, we characterized the impact of EAF and EAT on long-term freedom from arrhythmia in a cohort of patients having SRI for AF ablation. EAF and EAT were independent predictors of late AF and AT respectively after multivariate analysis. Early atrial fibrillation occurring late during the blanking period was associated with late AF recurrence, while the timing of EAT did not affect the late recurrence rates of AT.

Previous studies reported that 35–65% of patients develop early arrhythmia following AF ablation,^2,6,12 of which up to 69% develop late arrhythmia at follow-up.² However, previous studies utilized strategies that have spared much of the left atrial posterior wall from electrical isolation. Techniques have ranged from PV ostial ablation,² segmental ablation,¹³ and strategies isolating the PV antrum.^4,5,9,14 The impact of different ablation strategies on early recurrence was partly explored in the STAR-AF study that randomized 100 patients to PV isolation alone, CFAE ablation alone or both.¹⁵ The investigators found that PV isolation combined with CFAE ablation resulted in improved long-term results without an increase in early recurrences. However, the incidence and impact of early recurrence in a wide single ring PV isolation strategy has not been evaluated.

Our results show that SRI results in EAF in 28% patients. Long-term follow up demonstrates that patients with EAF were 3.5 times more likely to have LAF. Present results showing higher LAF rates in patients with EAF are consistent with past studies that utilized ostial,² segmental¹³, or circumferential⁹ lesion sets, showing an increased risk of LAF of between 1.5 and 4 times.

In this study, the rate of EAT was 25% and increased the risk of LAT by a factor of 5.6. However, EAT did not predict LAF. In fact the AF recurrence rate among patients with EAT was as low as patients without any early arrhythmia. In contrast, Choi et al.³ reported an EAT rate of 15.9% with an increased risk of AF among EAT patients after circumferential ablation. Differences in ablation strategies resulting in posterior left atrial isolation may account for different results. In a series of patients undergoing repeat ablation procedures following initial SRI, we previously reported that AT is frequently maintained by stable macro re-entrant circuits facilitated by gaps in long lines of lesions.¹⁶ In contrast, while minimizing macro re-entry tachycardia caused by line gaps, techniques involving isolation closer to the ostia may enable the posterior left atrium to participate in arrhythmogenesis. The posterior left atrium has been implicated in AF by previous studies.^17,18

Thus, differences in ablation strategies utilized may alter the predictive value of occurring during the blanking period. Early atrial tachycardia following SRI indicates patients at risk of LAT but not LAF. In contrast, EAF indicates patients at risk of LAF but not LAT.

Previous investigators have postulated that AF recurrence soon after ablation may be due to factors other than PV reconnection, including a transient inflammatory response to radiofrequency injury,^19,20 autonomic dysregulation following ablation²¹ and delayed scar maturation.²² In the largest reported series of patients with early arrhythmia, Themostoclakis et al. also observed an increased risk of late atrial arrhythmias if early arrhythmias occurred late in the blanking period.⁹ However, past studies have not explored the relationship between the early arrhythmia type and the time of occurrence. In this study, patients with EAF in the third month following ablation were at significantly higher risk of LAF compared with the first 2 months, despite the majority of EAF occurring in the first month. In contrast, LAT rates were similar regardless of EAT month. This suggests that transient factors that are more dominant immediately following ablation contribute to the mechanism of EAF. However, EAT in patients having SRI is likely to be maintained by stable re-entry circuits whose capacity for LAT is not influenced by time.

Multiple predictive factors of early recurrence have been reported: persistent AF,⁵ LA volume,^13,23 longer AF duration,⁹ hypertension,⁹ unsuccessful PV isolation,⁴ long procedure times,⁵ and structural heart disease.^4,24 Our study confirmed previously described predictors of recurrent arrhythmias. These factors are likely to reflect complex atrial substrate created by negative electro-anatomical modelling. We observed that unlike intraprocedural AF, intraprocedural AT was not associated with early arrhythmia. This is probably because circuits and foci that cause AT are more easily mapped and ablated during the procedure compared with AF.

Past studies have utilized a variety of blanking periods ranging from 2 weeks^2,13 to 3 months,^4,9 following ablation. The 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of AF suggest a 3-month blanking period following AF ablation.¹ Considerably higher rates of LAF in patients with early AF during the third month after ablation may justify shortening the blanking period from 3 to 2 months and may have significant implications for prognostication following AF ablation.

Limitations

The generalizability of these results pertaining to characteristics of EAF and EAT after SRI to a population of patients having other wide lesion sets is unclear. Secondly, it is possible that patients with LAT also had undocumented LAF. However, we utilized guideline-based monitoring to detect asymptomatic arrhythmia during follow-up. Finally, the number of patients with LAT in the third month is quite small. This may impact on the analysis and interpretation of results. However our findings are consistent with data from other studies that utilized different ablation strategies. Larger studies are needed to confirm our findings.

Conclusion

This study demonstrates that EAF and EAT predict different late arrhythmia types. Secondly, their timing during the blanking period has varying significance for future arrhythmic events following SRI. These observations suggest that it is important to determine early arrhythmia type occurring during the blanking period as it carries different prognostic and treatment implications.

Conflict of interest: none declared.

Funding

This work was supported by a project grant from the National Health and Medical Research Council of Australia (ID Nos: 512223). T.W.L. was supported by an Australian Postgraduate Award.

References