J Interv Card Electrophysiol DOI 10.1007/s10840-013-9864-9

Acute pulmonary vein reconnection is a predictor of atrial fibrillation recurrence following pulmonary vein isolation Elad Anter & Fernando M. Contreras-Valdes & Alexei Shvilkin & Cory M. Tschabrunn & Mark E. Josephson

Received: 1 November 2013 / Accepted: 20 November 2013 # Springer Science+Business Media New York 2014

Abstract Purpose Arrhythmia recurrence following pulmonary vein isolation (PVI) occurs predominantly due to the reconnection of previously isolated pulmonary veins (PVs). The prognostic implications of detection and treatment of acute PV reconnection are not well understood. We aim to examine the prognostic significance of acute PV reconnection on arrhythmia recurrence at 1 year following PVI. Methods This prospective study included 44 patients (22 men, 60±7 years) who underwent index PVI procedure for treatment of atrial fibrillation (AF). Acute PV reconnection and/or dormant PV conduction were assessed sequentially in response to a 30-min waiting period, intravenous isoproterenol infusion and/or adenosine. All cases of acute PV reconnection and/or dormant conduction were successfully targeted with additional ablation. Results Freedom from AF at 1 year was 75 % (83.3 % in paroxysmal and 65 % in persistent AF, p =ns). Acute PV reconnection and/or dormant conduction were evident in 16 of 44 patients (36.3 %). AF recurrence was documented in eight of 16 patients with, but only in three of 28 patients without acute reconnection (p = 0.009). Three patients underwent a redo procedure, all from the group of patients with acute PV reconnection. In a multivariate model, acute PV reconnection was a strong independent predictor of arrhythmia recurrence (hazards ratio [HR], 6.36; 95 % confidence interval [CI], 1.12–31.6).

E. Anter (*) : F. M. Contreras-Valdes : A. Shvilkin : C. M. Tschabrunn : M. E. Josephson Harvard-Thorndike Electrophysiology Institute, Division of Cardiovascular Disease, Beth Israel Deaconess Medical Center, Harvard Medical School, 85 Pilgrim Road, Baker 4, Boston, MA 02215, USA e-mail: [email protected]

Conclusion Identification of acute PV reconnection, even when successfully targeted, is a strong predictor of arrhythmia recurrence following PVI. Keywords Atrial fibrillation . Acute reconnection . Pulmonary vein isolation . Catheter ablation . Recurrence Abbreviations AAD Anti-arrhythmic drug AF Atrial fibrillation BMI Body mass index LA Left atrium LVEF Left ventricular ejection fraction OSA Obstructive sleep apnea PV Pulmonary vein PVI Pulmonary vein isolation

1 Introduction Pulmonary vein isolation (PVI) is an effective therapy for patients with symptomatic atrial fibrillation (AF) and is the cornerstone of ablation. However, arrhythmia recurrence is common and is accompanied by the inconvenient realization that durable PVI is difficult to achieve [1]. Pulmonary vein (PV) reconnection is a common feature in patients with recurrent AF after ablation and re-isolation can often facilitate arrhythmia freedom [2–4]. In addition, smaller studies indicate that patients without arrhythmia recurrence have fewer reconnected veins, suggesting chronic PV reconnection as the source of failed AF ablation [4]. PV reconnections are usually the result of small gaps in the ablation lesion set. This has been recently supported by histological data that correlated partial thickness radiofrequency ablation lesions with chronic and persistent PV conduction

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[5]. Although real-time assessment of lesion formation is lacking, data suggests that waiting period after PVI, isoproterenol and/or adenosine can unmask incompletely isolated PVs to reveal dormant reconnection or re-conduction that can be targeted for additional ablation [6, 7]. The premise of these methods to improve long-term PV isolation and clinical outcome resulted in several studies with varying results. While earlier reports showed improved longterm outcome following the use of adenosine to detect and treat dormant conduction when compared to historical cohorts [8–10], recent small prospective studies showed no difference [11] or a similar prognosis [12] in long-term freedom from AF between patients with paroxysmal AF with and without adenosine-reconnected PVs. The purpose of this study was to prospectively examine the prognostic value of treated acute PV reconnection induced by adenosine, isoproterenol, and/or a waiting period on 1-year outcome in patients with AF. The primary end point of the study was freedom from AF and/or organized atrial tachyarrhythmias at 1 year after a single ablation procedure.

2.2 Mapping and ablation protocol

This prospective study consisted of 44 consecutive patients with drug-refractory, symptomatic, paroxysmal or persistent AF who underwent index PVI between August 2011 and February 2012, and were followed for 12 months after the ablation procedure. AF was defined as paroxysmal or persistent according to the 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of AF [13]. Patients with persistent AF were only included if arrhythmia duration was less than 1 year, thus excluding long-term persistent AF patients. The study protocol was approved by the institutional review board of Beth Israel Deaconess Medical Center.

All anti-arrhythmic drugs (AADs) were discontinued for ≥5 half-lives (amiodarone was discontinued for ≥1 week) before the ablation procedure. All patients were anticoagulated for ≥1 month. Transesophageal echocardiography was performed to exclude atrial thrombi in all patients with persistent AF and in patients with ineffective anticoagulation during the 4 weeks preceding the ablation. The surface electrocardiogram and bipolar electrograms, filtered at 30–500 Hz, were continuously monitored and recorded on a computer-based digital recording system (Cardiolab system; Prucka Engineering, Houston, TX, USA). A phased array intra-cardiac ultrasound catheter (AcuNav, Diamond Bar, CA, USA) was placed in the right atrium. Two diagnostic decapolar catheters were positioned in the coronary sinus and the anterolateral right atrium. Unfractionated heparin was administered before the transseptal punctures to maintain an activated clotting time of 300–400 s for the duration of the procedure. The first transseptal puncture was performed via a long steerable sheath (Agilis; St. Jude Medical, Minneapolis, MN, USA) and the second via a fixed-curve long sheath (SL1; St. Jude Medical). The mapping/ablation catheter (Thermocool; Biosense Webster, Diamond Bar, CA, USA) was introduced into the left atrium (LA) through the steerable sheath while the circular mapping catheter (Lasso; Biosense Webster) was advanced into the LA over the fixed curve sheath. A wide antral approach was used to perform PVI at a distance of 2–3 cm from the pulmonary vein–left atrial junction (Fig. 1). Ablation of the left anterior PV was performed on the ridge between the vein and the appendage. The energy delivery settings were as follows: power, ≤40 W (≤20 W over the posterior left atrium); and temperature, ≤42 °C. Radiofrequency application was delivered for a maximum of 40 s to achieve an impedance decrease of 5–10 Ω at the ablation site; over the posterior LA, lesion duration was restricted to 20 s. Successful PVI was defined by the loss of PV potentials (entrance block) and failure to capture the LA during pacing

Fig. 1 Pulmonary vein isolation ablation strategy. Antero–posterior (left) and posterior–anterior (right) views of the left atrium. PVI was performed by isolating all pulmonary veins in a wide antral approach. Visitag (Carto

3, Biosense Webster) was used to annotate ablation lesions based on isochromatic scale corresponding to decrease in impedance (red signifies an impedance drop >5 %)

2 Methods 2.1 Study population

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from all bipoles of the Lasso catheter when positioned at the PV ostium (output, 10 mA; pulse width, 2 ms; exit block). Ablation in the PV carina was performed only when all the following criteria were met: (1) presence of LA–PV conduction despite completely encircling ablation lesions; (2) lack of near-field electrograms on the ablation line; and/ or (3) presence of near-field electrograms in the PV carina. All procedures were performed under general anesthesia.

2.3.1 Isoproterenol challenge Isoproterenol infusion was started at 3 μg/min with increments every 3 min to 6, 12, and 20 μg/min for an increase in heart rate of ≥50 %. In the majority of cases, concomitant infusion of phenylephrine hydrochloride was required due to hypotension. 2.3.2 Adenosine challenge

2.3 Detection of dormant conduction or re-conduction Entrance and exit block for each PV was confirmed after a ≥30-min waiting period from the time of the initial isolation. If persistent entrance and exit blocks were documented, intravenous isoproterenol, adenosine, or both were administered as follows: isoproterenol was the first agent of choice and was used in 36 patients (82 %). Adenosine was administered to patients who could not tolerate the hemodynamic effects of isoproterenol (39 %, 17/44). In addition, patients who tolerated isoproterenol, but did not have acute PV reconnection were subsequently treated with adenosine (21 %, 9/44). Fig. 2 Acute pulmonary vein reconnection. Each panel contains three surface electrocardiographic leads, ten bipolar electrograms of a circular mapping catheter positioned in the left superior pulmonary vein (PV), two right atrial (RA) electrograms and two coronary sinus (CS) electrograms. a Acute PV reconnection in response to adenosine. Adenosine produces transient atrioventricular block (red asterisk) and acute LA–PV reconnection (arrow). b Acute LA–PV reconnection in response to isoproterenol infusion (arrow)

Adenosine administration in a dose producing temporary atrioventricular conduction block during coronary sinus pacing (12–48 mg) was performed separately for each of the PV. In cases of common ipsilateral ostia, adenosine was given once per ipsilateral set of PVs. The effect of adenosine on LA–PV conduction was documented (Fig. 2). If adenosine induced persistent LA–PV conduction, the presence of conduction from the PV to the LA (exit) was also examined. In cases of persistent recovery of LA–PV conduction, further radiofrequency ablation was delivered until the vein was re-isolated. In cases of transient reconnection, ablation was performed anatomically, based on the earliest activation

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transiently observed using a circular mapping catheter. In all cases of reconnection, the same pharmacological challenge was repeated following a waiting period of at least 15 min, until all PVs remained isolated for ≥15 min. 2.4 Follow-up Following the ablation, patients resumed their pre-procedure medical regimen including AADs. Long-term follow-up consisted of clinic visits at 1, 3, 6 and 12 months and at least two 14-day sessions of trans-telephonic rhythm monitoring (with auto- and patient-trigger capabilities) at 3, 6 or 12 months. Additional trans-telephonic monitoring was performed based on symptoms. At each outpatient visit, patients were queried for symptoms and a 12-lead electrocardiogram was obtained. In the absence of any documented arrhythmias, AADs were discontinued between 1 and 3 months after the initial procedure. Patients with documented recurrence of atrial tachyarrhythmias were treated with AADs or offered repeat ablation procedures. In patients undergoing a repeat ablation, the same monitoring approach was used. The follow-up duration of the study was 1 year. 2.5 Statistical analysis Baseline clinical variables were compared between groups using two-sided Student's t-test (continuous variables) and Fisher's exact test (categorical variables). Event-free survival was estimated by the Kaplan–Meier survival function. Pairwise comparisons of survival rates were made using a log-rank test. The impact of the variables associated with the risk of AF recurrence on the 1-year AF-free survival end point (LA size, the presence of hypertension, persistent AF, and obstructive sleep apnea [OSA]) was assessed in a univariate model and the variables demonstrating significant association were entered in a multivariate model. Bootstrapping analysis was used for parameter estimation. A p value 3 cm) from the previously documented acute reconnection sites. At the redo procedure, only reisolation of the connected PVs was performed. These patients remained arrhythmia-free for the rest of the follow-up period (mean period 6±3 months).

3.4 Clinical variables associated with AF recurrence Acute PV reconnection and OSA were the only variables associated with AF recurrence in univariate analysis. In the Table 2 Univariate and multivariate analysis of clinical predictors of atrial fibrillation recurrence Variable

Hazards (95 % ratio confidence interval)

p value

LA dimension OSA Persistent AF Acute PV reconnection (univariate) Acute PV reconnection (multivariate)

1.03a 5.5 2.69 8.33 6.36

0.46 0.016 0.14 0.002 0.017

(0.97–1.04) 1.44–30.5 (0.65–11.1) (1.77–39.1) (1.12–31.6)

AF atrial fibrillation, LA left atrium, OSA obstructive sleep apnea a

Per millimeter increase in diameter

4 Discussion The main findings of this study are: (1) acute PV reconnections are common and their detection can be enhanced by a waiting period, isoproterenol and/or adenosine; (2) identification of acute PV reconnection, even when successfully targeted, is a strong predictor of arrhythmia recurrence following PVI; (3) in this cohort, acute PV reconnection was the only independent predictor of arrhythmia recurrence in a multivariate analysis, even when compared with the type of AT before ablation. The findings of our study are consistent with the recent report by Miyazaki and colleagues [12], and are extended also to patients with persistent AF. In their study, 109 patients with paroxysmal AF underwent PVI followed by pharmacological challenge with isoproterenol in conjunction with adenosine. Acute PV reconnections were documented in about one third

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of patients and then targeted with additional ablation until elimination of adenosine-dependent conduction. Recurrence of AF was significantly higher in subjects with acute PV reconnections compared to subjects without acute PV reconnection (49 % vs. 27 %, respectively; HR=1.37). Gula and colleagues published equally disappointing results using acute provocation with adenosine. In 76 consecutive patients, adenosine was administered after PVI and revealed transient reconnection in 35 % of subjects. In contrast to the study by Miyazaki et al., these patients did not receive additional ablation in an attempt to test the predictive power of adenosine for arrhythmia recurrence. There was in fact no difference in long-term freedom from AF between patients with and without adenosine-responsive veins, limiting the predictive utility of adenosine in long-term arrhythmia control [11]. Although the results of our study confirm the limited utility of acute PV reconnection ablation for long-term arrhythmia control, we found that acute PV reconnection is a strong predictor of arrhythmia recurrence. These different results may be explained by the following: (1) different patient population, as our study was not limited to subjects with paroxysmal AF and included an equal amount of subjects with persistent AF; (2) in the study by Gula et al. [11], patients who exhibited persistent reconnection in response to adenosine did not receive additional ablation until re-isolation; (3) perhaps, the most important difference between the studies was the method to detect reconnections. In our study, detection of reconnection was not limited to adenosine, and was detected by either a waiting period or isoproterenol in 62.5 % of all subjects. In this cohort of patients, acute PV reconnection was a stronger predictor for clinical recurrence when compared to the type of arrhythmia or left atrial dimension. This may be explained by the somewhat different patient population and ablation technique compared with our earlier cohort [14]. The current group of patients included subjects with either paroxysmal or early persistent AF according to the 2012 HRS/ EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of AF [13]. However, the group of persistent AF included patients with AF episode duration greater than 7 days requiring cardioversion, while patients with longterm AF (AF>1 year) were excluded. In addition, a wider circumferential ablation approach was used, resulting in greater substrate ablation. Lastly, acute PV reconnection was associated with early clinical recurrence, and thus may have attenuated the longer-term effects of other variables. Several studies examined the differential efficacy of waiting period, isoproterenol or adenosine on dormant PV conduction. Datino et al. [15] compared the differential efficacy of adenosine and isoproterenol in 25 subjects undergoing PVI. They found that adenosine was superior to isoproterenol in revealing dormant conduction (10 % vs. 87 %, p