1

Pulmonary Vein Antral Isolation and Nonpulmonary VeinTrigger Ablation without Additional Substrate Modification for

Treating Longstanding Persistent Atrial FibrillationDAVID LIN, M.D., DAVID S. FRANKEL, M.D., ERICA S. ZADO, P.A.-C., EDWARD

GERSTENFELD, M.D., SANJAY DIXIT, M.D., DAVID J. CALLANS, M.D., MICHAEL RILEY,M.D., MATHEW HUTCHINSON, M.D., FERMIN GARCIA, M.D.,

RUPA BALA, M.D., RALPH VERDINO, M.D., JOSHUA COOPER, M.D., and FRANCIS E.MARCHLINSKI, M.D.

From the Hospital of the University of Pennsylvania, Section of Cardiac Electrophysiology, Division of Cardiology, Department ofMedicine, Philadelphia, Pennsylvania, USA

PV Ablation for Persistent Atrial Fibrillation. Introduction: Effectiveness of antral pulmonaryvein isolation (PVAI) and ablation of non-PV triggers (non-PVTA) in controlling longstanding persistentatrial fibrillation (AF) has not been reported. We sought to describe clinical outcomes with this ablationstrategy in patients (pts) followed for at least 1 year.

Methods: Two hundred pts underwent PVAI for longstanding persistent AF and were followed forrecurrence. Thirty-three pts with <1-year follow-up and 37 pts with additional RF atrial ablation wereexcluded, leaving 130 pts for analysis.

Results: All 130 pts (108 men, mean LA 4.7 ± 0.6 cm, mean AF duration of 38 ± 44 months) underwentPVAI with entrance/exit block. In addition, 24 pts (15 pts during the initial procedure and 9 additionalpts at repeat ablations) had 40 non-PVTA, including 3 with AVNRT. During follow-up, atrial flutter (AFL)was noted in 7 (5%) pts. The AF-free survival after single procedure without antiarrhythmic drugs (AAD)was 38%. Repeat AF or AFL ablation was performed in 37 pts (28%) with PV reconnection uniformlyidentified (3.7 ± 0.5 veins/pt). During mean follow-up of 41.1 ± 23.8 months (range 12–103 months), 85/130pts (65%) were in sinus rhythm with 65 pts (50%) off AAD, 20 pts (15%) on AAD. Additionally, 9 pts (7%)have had rare episodes of AF such that 72% of pts have had good long-term clinical outcome. Of the 36 ptswith recurrent AF, 20 pts have not had a repeat procedure.

Conclusions: PVAI with non-PVTA for longstanding persistent AF provides good long-term AF controlin over 70% of patients with infrequent (5%) AFL. AAD therapy and repeat PVAI may be required forthis optimal outcome. (J Cardiovasc Electrophysiol, Vol. pp. 1-8)

antiarrhythmic drug, atrial fibrillation, catheter ablation, persistent atrial fibrillation, pulmonary vein isolation

Introduction

Ablation as a treatment modality for atrial fibrillation (AF)is widely accepted. As techniques and technologies improve,more patients with longstanding persistent AF are referredfor ablation. There is significant variability in ablation tech-niques and strategies.1-10 The reported outcome for controlof AF after a single ablation procedure ranges from 40%to 75%.11-14 The need for repeat ablation procedures, espe-cially for longstanding persistent AF is common, rangingfrom 30 to 60%.15-26 Much debate remains as to whether ad-ditional “empiric” lines of ablation or targeting regions with

Dr. Gerstenfeld reports participation on research grants supported byBiosense Webster and St. Jude Medcal. He has received honoraria relevantto this topic from Biosense Webster. Other authors: No disclosures.

Address for correspondence: David Lin, M.D., F.A.C.C., Hospital of theUniversity of Pennsylvania, 3400 Spruce Street, 9 Founders, Philadelphia,PA 19104, USA. Fax: +215-615-5441; Email: david.lin@uphs.upenn.edu

Manuscript received 06 November 2011; Revised manuscript received08 January 2012; Accepted for publication 24 January 2012.

doi: 10.1111/j.1540-8167.2012.02307.x

complex-fractionated atrial electrograms (CFAEs) should beperformed in the right and left atrium for patients with per-sistent forms of AF. The decision to proceed with extensiveleft atrial substrate ablation should be evidence based. Wesought to describe observations at the time of repeat ablationand long-term follow-up without additional empiric lines orablation.

We report long-term (>1 year) outcome in patients withlongstanding persistent AF who underwent only pulmonaryvein antral ablation procedures and are at least 1 year afterthe last ablation procedure.

Methods

From a period of November 2000 to December 2009,a total of 2050 patients underwent AF ablation. Of these,200 had longstanding persistent AF prior to the first ablationprocedure per the American College of Cardiology defini-tions.27-29 All patients were referred to the University ofPennsylvania Health System for catheter ablation of AF andsigned a written informed consent according to institutionalguidelines of the University of Pennsylvania Health Sys-tem. Demographic and clinical information was obtained,including age, gender, body mass index (BMI), time in

2 Journal of Cardiovascular Electrophysiology Vol. No.

TABLE 1

Baseline Patient Characteristics Stratified by Whether AF-Free SurvivalWas Achieved with One or More PVIs

AF Free with Failure ofOne or One or P

More PVIs More PVIs Value

N 85 45Age (years) 56.7 (9.3) 55.2 (9.4) 0.4Male (%) 81.2 86.7 0.5Hypertension (%) 50.1 66.7 0.09Coronary artery disease (%) 25.9 22.2 0.7Obstructive sleep apnea (%) 16.5 13.3 0.8Heart failure (%) 8.2 13.3 0.4Valvular heart disease (%) 11.8 8.9 0.8CHADS score 0.8 (0.9) 1.1 (0.9) 0.1Years since AF diagnosed 5.1 (4.8) 6.7 (5.8) 0.09Months in current episode of AF 35.2 (47.8) 37.7 (31.0) 0.7Left ventricular ejection fraction (%) 56.0 (10.5) 59.3 (9.6) 0.1Left atrial size (cm) 4.7 (0.6) 4.7 (0.7) 0.8Non-PV trigger targeted at index

ablation (%)27.1 20.0 0.4

Standard deviations are provided in parentheses.AF= atrial fibrillation; PVI= pulmonary vein isolation.

current episode of AF, and total duration of AF history, aswell as the presence of comorbid conditions such as hyperten-sion, coronary artery disease, diabetes, other structural heartdisease, sleep apnea, and history of stroke or transient is-chemic attack.

Patient characteristics are summarized in Table 1. Of the200 patients with longstanding persistent AF, 33 patientshad <1 year follow-up after the last ablation. An additional37 patients were enrolled in other studies involving additionalRF atrial ablation (CFAE ablation) or other substrate-basedanatomic ablation and were excluded from this study. There-fore, the study group comprises 130 patients for analysis.

Definitions

The primary outcome of the study is long-term freedomfrom AF of more than 1 year after the ablation (PVAI andnon-PVTA). Freedom from AF is defined as the absence ofAF or occurrence of a single-isolated AF episode per yearafter ablation with or without AAD. Secondary analyses in-cluded determination of predictors of time to AF recurrence,findings at time of repeat ablation, and incidence of atrialtachycardias. Since these were all patients with symptomaticlongstanding persistent AF, we also report a clinical end-point of AF control defined as fewer than 6 episodes of self-terminating AF per year and no more than one cardioversionper year.

Ablation Procedure

Antiarrhythmic drug therapy was stopped at least 5 half-lives before the patients were brought to the electrophysi-ology laboratory. Amiodarone was stopped at least 2 weeksprior to the procedure. Warfarin was typically discontinued1–3 days before the procedure and patients were routinelyadmitted the day prior to the procedure for intravenous hep-arin administration. All patients underwent transesophagealechocardiography prior to ablation. Patients underwent antralpulmonary vein antral isolation (PVAI) guided by intracar-

diac echocardiogram/circular multipolar electrode catheterrecordings and elimination of all provocable PV triggers andall non-PV triggers of AF (non-PVTA). Carina ablation le-sions were not routinely placed if the carina was dramaticallyrecessed as confirmed with intracardiac echo. We targeted thecarina only if (1) exit block could not be achieved with cir-cumferential antral ablation of the ipsilateral veins and earlypulmonary vein (PV) activation was recorded in the carina,and/or (2) reproducible triggers for AF from the carina re-gion were evident at the beginning of the case with attemptsat cardioversion. Intracardiac echocardiography (AcusonTM,Malvern, PA, USA) was used to guide transseptal puncture,ablation/circular mapping catheter placement, and lesion for-mation. Maneuvers to elicit PV and non-PVTA were per-formed before and after PVAI, which included (1) cardiover-sion of spontaneous AF to identify triggers associated withthe early recurrence of AF, (2) isoproterenol infusion of up to20 μg/min in incremental doses of 3, 6, 12, and 20 μg/min,(3) cardioversion of AF induced with rapid burst atrial pacingduring low dose isoproterenol infusion, 2–3 μg/min. Any re-producible PV APD with or without AF initiation confirmedwith the multipolar mapping catheter was considered a PVtrigger. For non-PV triggers the initiation of AF or atrialtachycardia (defined as tachycardia that lasted >30 seconds)or less commonly the initiation of reproducible, frequent andrepetitive non-PV APDs was required. Successful pulmonaryvein antral isolation was defined as loss of PV potentials (en-trance block) and local PV capture without capture of theleft atrium when pacing (10 mA and 2 ms pulse width) eachelectrode pair of the 10 pole circular mapping catheter placedat the ostium of the PVs just distal to the RF ablation lesions(exit block). PVs were reassessed for entrance and exit blockwith the circular mapping catheter at least 20 minutes afterinitial isolation and veins were reisolated if acutely recon-nected. Patients with a clinical history of typical right atrialflutter or induced typical atrial flutter during the ablation pro-cedure also underwent cavotricuspid isthmus ablation. Theablation endpoint was both persistent PV isolation and noAF with repeat incremental infusion of up to 20 mcg/minof isoproterenol. All non-PV were targeted with an end-point of inability to provoke the trigger with repeat isopro-terenol infusion. Patients with spontaneous macroreentrantatrial tachycardias/flutter had the circuit defined using acti-vation and/or entrainment mapping to guide appropriate ab-lation strategy. In the absence of atrial tachycardias/flutters,no empiric lines were performed. Empiric substrate-basedablation was not performed either during the initial or withrepeat procedures. Seventeen patients were a small part ofthe total patient enrollment in the RASTA study.30 The pa-tients enrolled in RASTA included patients with persistentand longstanding persistent AF. One of the treatment arms inthe RASTA study targeted the common anatomic locations ofidentified non-PV triggers in addition to a standard ablationprotocol that included antral PV isolation plus eliminationof induced non-PV triggers. Briefly, following PVAI, addi-tional empiric lesions to known common sites of atrial tachy-cardia origin were given using 3D electroanatomic guidanceat the following locations using a standardized protocol forall operators, (1) lesions extending from 3 o’ clock to 8 o’clock at or immediately behind the mitral annulus, (2) le-sions at the limbus of the fossa ovalis from both the LA andright atrium, (3) lesions at the eustachian ridge and posteriorostium of the coronary sinus, (4) lesions along the middle

Lin et al. PV Ablation for Persistent Atrial Fibrillation 3

and lower third of the crista terminalis (CT), and (5) lesionsencircling the superior vena cava (SVC) without necessar-ily achieving isolation if there was a risk of phrenic nerveinjury or injury to the sinus node. The endpoint of lesion de-livery was local electrogram attenuation achieving power of≥20 W for at least 20 seconds with concomitant 5–10 Ω dropin impedance. The defined endpoint of electrogram attenu-ation was achieved in all 17 patients that were included inthis analysis. The sites targeted with lesions were designed toeliminate common trigger sites while avoiding the creationof lines to minimize the potential for additional macroreen-trant circuits. These 17 patients with longstanding persistentAF were included for completeness because no additionalsubstrate-based ablation was performed.

Patients undergoing repeat procedures had all 4 PVs iso-lated/reisolated and underwent the same ablation protocolwith respect to provocation of non-PV triggers and endpointsfor ablation as described for the original ablation procedure.

Follow-Up

After ablation, patients were routinely prescribed antiar-rhythmic drugs (AAD) and warfarin. The first 90 days postab-lation was censored for the purposes of determining outcome.Amiodarone was typically replaced with a different AAD un-less other AADs were contraindicated or not tolerated. Pre-ablation, there were 15 patients (12%) on amiodarone and atotal of 3 patients (2%) who received amiodarone at any timepostablation. For patients without structural heart disease, aclass IC agent was typically used. Since these were all pa-tients with longstanding persistent AF, AAD were typicallycontinued for at least 6 months. In some patients, AADs werecontinued beyond this point based on doctor and/or patientpreference even in the absence of an arrhythmia event. Pa-tients in this study were all followed for at least 1 year sincethe most recent ablation with extensive outpatient transtele-phonic and ECG monitoring and office visits at 6–8 weeks,6 months, and 1 year. The patients were routinely providedwith a 30-day autotrigger transtelephonic monitor (TTM)that detects both symptomatic and asymptomatic AF. Patientswere instructed to transmit twice daily ECG recordings andadditionally with symptoms during several time periods: (1)at 6–8 weeks or when AAD were discontinued, and (2) at6 months. Patients were provided with an additional TTMif they had any arrhythmia symptoms at any time duringfollow-up. Twelve-lead ECG was obtained at each visit andechocardiogram typically performed at the first 2 visits. Pa-tients were contacted by telephone at least every 6 months ifnot followed at our institution beyond the first year of follow-up. Source documentation of any recurrent arrhythmia wassought. However, arrhythmia recurrence was assumed basedon recurrence of any symptoms and or asymptomatic ECGdocumented arrhythmia recurrence.

Statistical Analysis

Continuous variables were expressed as means with stan-dard deviations and categorical variables are expressed aspercentages. The Student’s t-test and Pearson’s chi-squaretest were used to compare continuous and dichotomous vari-ables, respectively, between groups. Multivariate logistic re-gression was utilized to identify predictors of time to AFrecurrence. Variables analyzed included age, male sex, hy-pertension, coronary artery disease, obstructive sleep ap-

nea, heart failure, valvular heart disease, CHADS2 score,years since AF diagnosis, months in current episode ofAF, left ventricular ejection fraction, left atrial size, andnon-PV triggers targeted. Analyses were performed usingSPSS software (version 16.0, SPSS Inc., Chicago, IL, USA).A P value ≤ 0.05 was considered statistically significance.

Results

Of the 130 total patients in the group, there were 108men (83%) with a mean LA size of 4.7 ± 0.6 cm and meanduration of continuous AF prior to the ablation procedureof 38 ± 44 months (range 12–360 months) with a medianduration of 24 months. During the initial procedure, PVAIwas performed in all patients to achieve acute entrance andexit block. Some ablation in the carina region was performedin 49% of ipsilateral veins and 64% of the study patients.Fifteen patients had 1 or more non-PV triggers targeted: 5patients with atrial tachycardia (AT) or AF, 3 patients withrepetitive APDs, 4 patients with both AT or AF and APDsfrom separate area, and 3 with sustained AVNRT. TargetedATs or AF/repetitive APDs were from superior vena cava(5/1), posterior wall LA (0/2) fossa ovalis (3/0), mitral an-nulus/CS (2/0), and crista terminalis/Eustachian ridge (3/4).The 3 patients with sustained AV nodal reentrant tachycardiaunderwent successful slow pathway ablation. Seventeen pa-tients had empiric lesions to typical triggering sites as part ofa separate study protocol as previously described.30 Outcomeresults and multivariate analyses performed with and withoutthese patients included were not different and therefore thesepatients were included in all analyses. Twelve patients alsohad cavotricuspid isthmus (CTI) ablation for a history of orinducible typical right atrial flutter.

The single procedure efficacy for freedom from AF andatrial flutter without AAD was 38% and improved to 48%with the addition of an AAD. Thirty-seven of the 130 (28%)patients and 37 of 63 (59%) patients with recurrences under-went at least 1 repeat ablation. The mean number of proce-dures was 1.3 ± 0.6, median 1, range 1–3. Pulmonary veinreconnection was documented in 36 of the 37 patients un-dergoing repeat ablations with a mean of 3.1 reconnectedpulmonary veins per patient. A total of 12 patients had non-PV triggers identified at the time of the repeat procedure, 3patients had the same or different sites targeted in the firstprocedure and 9 additional patients had new non-PV triggersites identified. The distribution of non-PV triggers (AT orAF/repetitive APDs) at the time of repeat ablation was asfollows: superior vena cava (3/0), posterior wall LA (1/0),fossa ovalis (2/0), coronary sinus/mitral annulus (4/1), cristaterminalis/Eustachian ridge (5/1). Seven patients had CTI ata repeat procedure and 5 had left atrial line(s) for clinicallydocumented left atrial flutter. Of the patients with non-PVtargets initiating AF, all had efficacy as indexed by inabilityto reinitiate AF with repeat isoproterenol infusion challenge.

Ninety-eight percent of patients had 1, 69% had 2, and31% had 3 extended periods of transtelephonic monitoringand/or had an implanted pacemaker for monitoring duringfollow-up. The most common reason for attrition in repeatmonitoring was documentation of recurrent AF.

During mean follow-up of 38.7 ± 22.8 months (range12–103 months) following the last procedure, 85 of 130 pa-tients (65%) remained in sinus rhythm of which 65 (50%)were off antiarrhythmic drugs and 20 (15%) remained on

4 Journal of Cardiovascular Electrophysiology Vol. No.

Figure 1. Long-term outcome following the last ablation procedure. AF=atrial fibrillation; AAD= antiarrhythmic drugs; Rare AF defined as <6episodes per 12 months and no more than 1 cardioversion in 1 year.

Figure 2. Atrial fibrillation free survival with single catheter ablation.

AAD, some due to patient and/or physician preference with-out document AF recurrence. An additional 9 patients (7%)met criteria for our clinical endpoint of AF control (<6nonsustained AF episodes/year and <1 cardioversion/year),such that overall, 72% of patients have had good long-termclinical outcome (Fig. 1).

AF free survival is illustrated for single (Fig. 2) and mul-tiple procedures (Fig. 3), as well as AF control for multi-ple procedures (Fig. 4). There was a nonsignificant trendtoward greater AF control for multiple procedures amongthose with PVAI and non-PV triggers targeted, compared tothose with PVAI only (Fig. 5, P = 0.1). The analysis com-paring AF free survival in those patients with versus withoutnon-PV triggers targeted did not show a significant differ-ence. Of note, 20 of the 36 patients with recurrent AF notcontrolled with AADs have not had a repeat procedure. Theincidence of postablation atrial tachycardia and reentrant leftatrial flutter, excluding the 90 day postablation blanking,was 5.3% (7/130). Hypertension and years since AF diag-nosis both significantly predicted time to recurrence of AF(Table 2).

Figure 3. Atrial fibrillation free survival with 1 or more catheter ablations.

Figure 4. Atrial fibrillation control with 1 or more catheter ablations.

Discussion

Since the original seminal observation by Haissaguerreand colleagues in 199831 of pulmonary vein triggers for AF,the technique of catheter-based ablation of AF has continuedto evolve. It is fairly well established that pulmonary veinisolation alone for paroxysmal AF can achieve reasonablygood long-term success.5,14 As newer technologies becomeavailable and techniques improve, the indications for AF ab-lation have broadened to include much sicker patients andthose with more persistent AF. However, unlike paroxysmalAF, the search for the best strategy for ablation of long-standing persistent AF has proven more elusive, with highlyvariable ablation techniques and reported outcomes. Manyoperators employ some combination of encircling of the PVs(with entrance block) as the foundation of the ablation pro-cedure in conjunction with empiric left atrial lines or target-ing of other atrial anatomic substrate.9 Whether additional“substrate modification” by empiric linear right and left atrial

Lin et al. PV Ablation for Persistent Atrial Fibrillation 5

Figure 5. Atrial fibrillation control withone or more catheter ablations, stratifiedby whether nonpulmonary vein triggerswere targeted.

TABLE 2

Univariate Predictors of Time to Atrial Fibrillation Recurrence FollowingOne or More PVIs

Hazard 95% Confidence PRatio Interval Value

Age (per 1 year increase) 0.99 0.96–1.02 0.6Male 0.78 0.33–1.86 0.6Hypertension 1.81 0.97–3.38 0.06Coronary artery disease 0.79 0.39–1.59 0.5Obstructive sleep apnea 0.79 0.33–1.86 0.6Heart failure 1.45 0.61–3.42 0.4Valvular heart disease 0.96 0.34–2.68 0.9CHADS score (per 1 point increase) 1.19 0.93–1.54 0.2Years since AF diagnosed (per 1 year

increase)1.05 1.00–1.10 0.06

Months in current episode of AF (per1 month increase)

1.00 0.99–1.01 0.5

Left ventricular ejection fraction (per1% increase)

1.03 0.99–1.06 0.1

Left atrial size (per 1 cm increase) 0.95 0.57–1.58 0.8Non-PV trigger targeted at index

ablation0.75 0.36–1.57 0.4

∗In multivariate modeling, hypertension and years since AF diagnosedboth remained significantly associated with atrial fibrillation recurrence(P= 0.02 and 0.01, respectively).PVI= pulmonary vein isolation; AF= atrial fibrillation.

lines, targeting of CFAEs, or other anatomic structures con-fers any incremental benefit remains an area of active debate.

In our series, using a technique of ablation of the PVantrum to achieve entrance and exit block and targeting ofnon-PV triggers, without any additional empiric lines or em-piric anatomic ablation, we were able to achieve good long-term control of longstanding persistent AF. While some pa-tients did require more than one ablation to achieve the goal,almost universally, recurrent AF was associated with recon-nection of the PVs and reisolation of the reconnected PVsand elimination of any other identifiable non-PV triggers

achieved successful control of the AF, albeit with adjunctiveantiarrhythmic therapy required in a significant minority.

Comparison to Previous Reports

There are few prospective, randomized studies comparingthe different strategies for ablation of longstanding persistentAF. In a randomized study reported by Elayi and colleagues,3 different strategies for ablation of longstanding persistentAF were compared: (i) anatomic circumferential PV abla-tion without confirmation of electrical isolation (ii) PVAIwith entrance block and (iii) hybrid approach of PVAI andablation of CFAE.17 There were 48 patients in the PVAIgroup with a mean follow-up of 16.4 months. The singleprocedure efficacy for the PVAI was 40% and was inferiorto that noted for PVAI and CFAE ablation at 61%. However,the AF free outcome with PVAI alone improved to 56% afterrepeat procedures in 40% of the patients with 83% of thepatients demonstrating AF control with the addition of anAAD. The good clinical outcome with repeated PVAI plusAAD, 83% freedom from AF, approached that of repeatedPVAI and CFAE ablation plus AAD therapy, 94% freedomfrom AF, in the Elayi experience. Of note, fewer of the pa-tients in the PVAI alone arm in their study underwent repeatablation (40% vs 53%) and almost all for AF and not atrialtachycardia. The results in their PVAI plus AAD therapygroup are consistent with the outcome we report in patientswith longstanding persistent AF. The incidence of postabla-tion AT in their study for patients treated with PVAI alonewas also similarly low at about 7%. A shorter mean follow-up of 16.4 months may account for the slightly better overalloutcome in their report after repeat ablation procedures forpatients treated with PVAI alone. Other distinctions worthnoting between studies include the fact that, non-PV triggerswere not routinely targeted, the SVC was targeted wheneverPV-like potentials were present, and the endpoint for PVAIincluded entrance block with exit block only for some veins.

Another randomized study by Oral and colleagues in-volving 50 patients in each arm, compared PVAI and

6 Journal of Cardiovascular Electrophysiology Vol. No.

PVAI + CFAE in patients with longstanding persistent AF.There was no significant difference in the single procedureefficacy between the 2 arms, which was 38% and 34%, re-spectively.21 Fifty-eight percent of the patients in the PVAIarm underwent repeat ablations in order to achieve efficacyof 68% with mean of 9-month follow-up. All patients hadPV reconnection at time of repeat procedure. These resultsare similar to what we observed in the current report.

A more recent observational study by Tilz and colleaguesreported experience in 205 patients who underwent catheterablation of longstanding persistent AF with a mean follow-up of 19 months using a strategy of PVAI and PVAI + CFAEif direct current cardioversion post-PVAI failed to restoreSR.19 Pulmonary vein antral isolation was the sole ablationstrategy in 82% of the patients during the initial procedure.The single procedure efficacy was 28% and improved to 34%with AAD. Forty-nine percent of patients underwent repeatablation and 80% had reconnected PVs at time of repeat pro-cedure. Patients who underwent repeat ablation proceduresunderwent repeat isolation of reconnected PVs and in somepatients, CFAE ablation, linear lesions for AT, and SVC iso-lation. In their series, including the repeat ablations, PVAIwas performed as sole therapy in 60.5% with 69.4% of pa-tients remaining in SR after mean follow-up of 19 months. Incontrast, in our series, the single procedure primary endpointwas 38% without AAD and improved to 48% with AAD.After a mean of 1.3 (range 1–3) procedures and with greaterthan 12 months from the last procedure, we achieved theprimary endpoint of freedom from AF in 50% (65 of 130)without drugs and improved to 65% with AAD with meanfollow-up of 39 months. An important distinction from theTilz series is that we did not perform additional empiric linesor CFAE ablation even at the time of repeat ablation. Lin-ear lesions were placed only in the presence of documentedmacroreentrant atrial flutter. Pulmonary vein antral ablationremained the foundation of the procedure and non-PVTAwas targeted only when demonstrated to trigger AF eitherspontaneously or with provocation maneuvers described ear-lier. Furthermore, when considering that all the patients inthe current study were highly symptomatic with longstand-ing persistent AF, it is reasonable to consider the secondaryendpoint of AF control, which we defined as fewer than 6episodes of AF over a 12-month period and not requiringmore than one cardioversion in the same period. Using theclinical endpoint of AF control, an additional 9 patients (7%)had rare episodes of AF, such that overall, 72% of the pa-tients had good long-term clinical outcome. In addition, ofthe 36 patients without good long-term clinical outcome,20 have not had a repeat ablation. Since not all patientswith recurrent AF have undergone repeat ablations, the ac-tual efficacy of PVAI with non-PV trigger ablation may beunderestimated.

Of importance is the fact that in the series by Elayiet al., Oral et al., and Tilz et al., the results were compa-rable to ours despite the absence of additional empiric linesor ablation of CFAE in our study population. These find-ings would suggest that in the absence of data that show aclear advantage with empiric linear ablation and ablation ofCFAE sites, our primary efforts should be to identify waysto provide durable long-term PVAI. In select patients withseverely diseased atria, there may be the need to target addi-tional anatomic or electrically abnormal atrial myocardium.However, in the majority of patients with recurrent AF af-

ter an ablation, pulmonary vein reconnection is present andremains the probable triggering mechanism for most AF.

Role of Non-PV Triggers

We identified non-PV triggers in 24 patients (18.5%) inour study population. Interestingly, 3 patients had AV nodalreentrant tachycardia that could have played a role in initialAF triggering earlier in the clinical course. Because of thechronicity of the AF all veins were of course also isolated inaddition to AV nodal slow pathway modification.

Of note, our study was not designed to prospectively andspecifically assess the role of non-PV trigger ablation onclinical outcome in this patient group. Nevertheless, our posthoc analysis would suggest that there appears be a modestbenefit in eliminating these triggers and targeting the CTIif RA flutter is observed (Fig. 5). More investigation willbe required to confirm the importance of targeting non-PVtriggers.

Impact on Development of LA Flutter

By limiting the ablation strategy to the pulmonary veinsand non-PV sites only when identified as a trigger, the poten-tial for creating iatrogenic circuits that could sustain recurrentatrial flutters is minimized. The incidence of postablation ATwas 7% with PVAI only in the series reported by Oral andcolleagues and 5% in our series with PVAI and non-PV trig-ger ablation.21 Of note, in the report by Tilz and colleaguesthe incidence of LA flutters post-AF ablation was 13%with additional LA ablation (CFAE) and lines in 14% and71%, respectively performed at the time of repeat ablationprocedures.19

Strategy at Repeat AF Ablation

There is a natural tendency to do more when there is re-current AF after the original AF ablation procedure and oursis the only study group where repeat ablation mimicked theinitial procedure. However, there are several reasons that ad-ditional lines and empiric substrate ablation usually are notnecessary. First, reconnection of PVs is the rule in the settingof recurrent AF and most triggers provoking AF with isopro-terenol infusion arise from the PVs and the remaining fromnon-PV sites can be easily identified. Second, much of theAF substrate (CFAEs, ganglionated plexus, atrial debulk-ing, etc.) can be achieved by antral ablation with effectiveproximal PV isolation. Finally, the true anatomic fibrillatorysubstrate is ill defined and can vary from patient to patientmaking selection of a specific anatomic target difficult. Ourstudy would suggest that the appropriate focus even at thetime of repeat ablation is to effectively isolate the pulmonaryveins and eliminate non-PV triggers.

Limitations

This is an observational study. However, our approach toablation of AF has been a consistent systematic approachwith the endpoint of isolation of the pulmonary veins withentrance and exit block and targeting of non-PVTA withoutadditional empiric lines. We have used the same standardizedstimulation protocol consisting of isoproterenol infusion, AFinduction and pacing to identify triggers for AF both at thetime of initial ablation as well as the repeat study, thereforemaking this one of the largest study populations with the

Lin et al. PV Ablation for Persistent Atrial Fibrillation 7

most extensive follow-up, using a consistent approach forthe entire duration of the study.

We also included the secondary endpoint of AF controlwith or without medication. However, since the study popu-lation are all patients with highly symptomatic longstandingpersistent AF preablation, we feel that in addition to the pri-mary endpoint of long-term freedom from AF, the secondaryendpoint of AF control is an important clinical endpoint giventhe marked symptom improvement.

As anticipated, compliance with monitoring at each inter-val was not uniform. However, the majority of patients didcomplete 2 extended transtelephonic monitors. In addition,most of the attrition in additional monitoring was related todocumented AF recurrences obviating the need for additionalmonitoring. Furthermore, all patients were followed at reg-ular intervals in addition to the extended ECG monitoring.Routine 12-lead ECGs were documented with each officevisit and patients were taught to check their pulse regularlyand contact their provider if recurrent symptoms or any pulseirregularity for additional ECG assessment.

Conclusions

Our experience in patients with longstanding persistentAF undergoing PVAI plus ablation of non-PV triggers with-out additional empiric lines or targeting of CFE sites supportthe following: (1) effective PVAI and non-PV trigger abla-tion results in AF control in >70% of patients and eliminatesthe need for AADs in approximately 50%; (2) by limitingthe destruction of atrial tissue, the potential for iatrogenicsymptomatic atrial tachycardias and flutters postablation isinfrequent (5%); (3) although more than one-third of patientsrequired repeat ablations, effective AF control seems to belong-lasting in most patients; and (4) since PV reconnectionat repeat ablation is the rule and not all patients with recur-rent AF undergo repeat ablations, the actual efficacy of PVAIwith non-PV trigger ablation may be underestimated.

References

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