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Complexity and Distribution ofDrivers in Relation to Duration ofPersistent Atrial Fibrillation

Han S. Lim, MBBS, PHD,a Mélèze Hocini, MD,a,b Remi Dubois, PHD,a,b Arnaud Denis, MD,a,b Nicolas Derval, MD,a,b

Stephan Zellerhoff, MD,a Seigo Yamashita, MD,a Benjamin Berte, MD,a Saagar Mahida, MBCHB,a Yuki Komatsu, MD,a

Matthew Daly, MBCHB,a Laurence Jesel, MD,a Carole Pomier, PHD,a,b Valentin Meillet, MSC,a,b Sana Amraoui, MD,a,b

Ashok J. Shah, MD,a Hubert Cochet, MD,a,b Frédéric Sacher, MD,a,b Pierre Jaïs, MD,a,b Michel Haïssaguerre, MDa,b

ABSTRACT

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BACKGROUND The underlying mechanisms sustaining human persistent atrial fibrillation (PsAF) is poorly understood.

OBJECTIVES This study sought to investigate the complexity and distribution of AF drivers in PsAF of varying

durations.

METHODS Of 135 consecutive patients with PsAF, 105 patients referred for de novo ablation of PsAF were prospectively

recruited. Patients were divided into 3 groups according to AF duration: PsAF presenting in sinus rhythm (AF induced),

PsAF <12 months, and PsAF >12 months. Patients wore a 252-electrode vest for body surface mapping. Localized drivers

(re-entrant or focal) were identified using phase-mapping algorithms.

RESULTS In this patient cohort, the most prominent re-entrant driver regions included the pulmonary vein (PV) regions

and inferoposterior left atrial wall. Focal drivers were observed in 1 or both PV regions in 75% of patients. Comparing

between the 3 groups, with longer AF duration AF complexity increased, reflected by increased number of re-entrant

rotations (p < 0.05), number of re-entrant rotations and focal events (p < 0.05), and number of regions harboring

re-entrant (p < 0.01) and focal (p < 0.05) drivers. With increased AF duration, a higher proportion of patients had

multiple extra-PV driver regions, specifically in the inferoposterior left atrium (p < 0.01), superior right atrium

(p < 0.05), and inferior right atrium (p < 0.05). Procedural AF termination was achieved in 70% of patients, but

decreased with longer AF duration.

CONCLUSIONS The complexity of AF drivers increases with prolonged AF duration. Re-entrant and focal drivers are pre-

dominantly located in the PV antral and adjacent regions. However, with longer AF duration, multiple drivers are distributed at

extra-PV sites. AF termination rate declines as patients progress to longstanding PsAF, underscoring the importance of early

intervention. (J Am Coll Cardiol 2017;69:1257–69) © 2017 by the American College of Cardiology Foundation.

A trial fibrillation (AF) is traditionally thoughtto be sustained by multiple random re-entrant wavelets (1,2). The discovery that

pulmonary vein (PV) ectopy triggers spontaneousinitiation of AF has led to the isolation of PV triggersas a cornerstone in AF ablation, particularly in

m the aHôpital Cardiologique du Haut-Lévêque, CHU Bordeaux, Universit

SERM U1045 - L’Institut de Rythmologie et Modélisation Cardiaque LIRY

rt by Dr. Lim as a Samuel A. Levine Young Clinical Investigator Award Fin

sociation (Chicago, Illinois, 2014). This work was supported by the Agence N

U-04, ANR Tempo, Leducq Foundation, and European Frame Programme

rly Career Fellowship from the National Health and Medical Research Cou

n stock in CardioInsight. Drs. Dubois and Shah are paid consultants of Cardi

rdioInsight. All other authors have reported that they have no relationship

nuscript received April 26, 2016; revised manuscript received January 10

paroxysmal AF (3). The underlying mechanisms sus-taining persistent AF (PsAF), however, are less wellunderstood. This has resulted in a wide variation incurrent ablation and surgical therapies for PsAF.There is growing evidence that localized re-entrantand focal sources drive the rest of the atria during

é Victor Segalen Bordeaux II, Bordeaux, France; and

C, Bordeaux, France. This research was presented in

alist at the Scientific Sessions of the American Heart

ationale de la Recherche (ANR) under grant ANR-10-

7. Dr. Lim is supported by the Neil Hamilton Fairley

ncil of Australia. Drs. Hocini, Jaïs, and Haïssaguerre

oInsight. Dr. Pomier is an employee ofMedtronic and

s relevant to the contents of this paper to disclose.

, 2017, accepted January 12, 2017.

ABBR EV I A T I ON S

AND ACRONYMS

AF = atrial fibrillation

DF = dominant frequency

IQR = interquartile range

LA = left atrium

LAA = left atrial appendage

Pers<12m = persistent atrial

fibrillation with the longest

episode of continuous atrial

fibrillation lasting <12 months

Pers>12m = longstanding

persistent atrial fibrillation

with continuous atrial

fibrillation >12 months

PersSR = persistent atrial

fibrillation presenting in sinus

rhythm

PsAF = persistent atrial

fibrillation

PV = pulmonary vein

RA = right atrium

RPV = right pulmonary vein

Lim et al. J A C C V O L . 6 9 , N O . 1 0 , 2 0 1 7

Complexity and Distribution of Drivers in Prolonged AF M A R C H 1 4 , 2 0 1 7 : 1 2 5 7 – 6 9

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PsAF (4–10). Localized sources in AF withdominant and multiple unstable re-entrantcircuits and spatiotemporal periodic activityhave been demonstrated in experimental ani-mal studies (4–6). In humans, high-densitymultielectrode catheter mapping detecteddiscrete localized sources driving AF in pa-tients with prior ablation (7), and spectralanalysis identified sites of high-frequency ac-tivity maintaining human AF (8). Recently,rotor activity and focal sources were identi-fied with the use of basket catheters andcomputational mapping (9). In surgicalstudies, epicardial mapping of chronic AF pa-tients revealed an area of regular rapidrhythm as the commonest underlyingpattern (10).

SEE PAGE 1270

Noninvasive mapping provides additionalinsights into the mechanisms underlying AF.Traditional point-by-point mapping is limited

in AF whereby the activation sequence changesdynamically. Invasive multielectrode mapping with aroving catheter provides valuable information but isunable to map global biatrial activation (7). Humansurgical studies enable detailed epicardial mapping,but are limited to regions accessible during surgery(10). Noninvasive phase mapping allows high-resolution simultaneous recording of biatrial AF acti-vation sequences under circumstances close to normalphysiological conditions. The present study aimed toinvestigate the effect of AF duration on the character-istics and anatomical distribution of re-entrant andfocal drivers in a large consecutive cohort of patientswith PsAF without prior ablation.

METHODS

A detailed description of the methods is provided inthe Online Appendix.

STUDY POPULATION. We prospectively recruitedconsecutive patients undergoing catheter ablation forpersistent and longstanding PsAF. Of 135 consecutivepatients with PsAF, 30 were excluded due to previousAF ablation. Patients were divided into 3 clinicallydefined groups: 1) PsAF presenting in sinus rhythm(PersSR); 2) PsAF with the longest episode of contin-uous AF lasting <12 months (Pers<12m); and 3) long-standing PsAF with continuous AF >12 months(Pers>12m). All patients provided informed consent tothe study protocol, which was approved by the insti-tutional Clinical Research Ethics Committee.

NONINVASIVE BODY SURFACE MAPPING. Themethodology is previously described in detail (11,12).We used a commercially available noninvasive map-ping system (ECVue, Cardioinsight Technologies,Cleveland, Ohio) to provide panoramic beat-to-beatmapping. In brief, a 252-electrode vest was appliedto the patient’s torso. Noncontrast thoracic computedtomography scan was performed to obtain high-resolution 3-dimensional images of the individualbiatrial geometry. Unipolar electrograms from torsopotentials were reconstructed during each beat orcycle using mathematical algorithms and projectedon the biatrial shell (11). Consecutive windows(average 9 � 2 windows) with long R-R pauses($1,000 ms) during AF were recorded.

In 32 patients, consecutive recordings up to 20windows (totaling 20,000 ms) were acquired. Thedetected re-entrant and focal driver regions overvarying recording durations (1 to 19 windows; 1,000to 19,000 ms) were examined to determine theoptimal recording durations. After 10,000 ms ofrecording, 96.1 � 10.0% of re-entrant driver regionsand 95.3 � 12.9% of focal driver regions were identi-fied compared with the total recording duration of20,000 ms (Figure 1, Online Figure 1).

Activation maps were computed using the tradi-tional unipolar electrogram intrinsic deflection-based(-dV/dTmax) method. Maps of AF were generatedusing algorithms combining phase mapping andfiltering to eliminate artifacts in signal morphology(11,12). Localized AF drivers were classified as focal(with $2 repetitive focal activity) when a wavefrontoriginated from a focal site with centrifugal activationand confirmed by a QS pattern on unipolar electro-grams; or re-entrant (with $2 rotations) when at least2 waves fully rotated around a functional core onphase progression and were verified by sequentialactivation of local unipolar electrograms covering thelocal cycle length around a pivot point.

The computed tomography–based geometry wasdivided into 7 regions to provide anatomical classifi-cation for aggregated driver-density maps: region 1,left PVs/left atrial appendage (LAA); region 2, rightPVs (RPVs)/posterior septum; region 3, posterior andinferior LA and the coronary sinus ostium; region 4,superior right atrium (RA); region 5, inferior RA;region 6, anterior LA/roof; and region 7, anterior LA/anteroseptal. Each region was further subdivided intosubregions to delineate the anatomical structures(Central Illustration, Online Appendix, Online Figures2 to 6).

STATISTICAL ANALYSIS. Categorical variables areexpressed as numbers (%). Continuous data are

FIGURE 1 Detection Rate of Driver Regions Over Recording Duration

100

75

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00 2 4 6 8 10 12 14 16 18 20

% D

river

Reg

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Det

ecte

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Re-entrant

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75

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00 2 4 6 8 10 12 14 16 18 20

% D

river

Reg

ions

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d

Duration (secs)

Focal

A

B

Percentage of (A) re-entrant driver regions and (B) focal driver regions

identified with varying recording durations (1,000 to 20,000 ms).

J A C C V O L . 6 9 , N O . 1 0 , 2 0 1 7 Lim et al.M A R C H 1 4 , 2 0 1 7 : 1 2 5 7 – 6 9 Complexity and Distribution of Drivers in Prolonged AF

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expressed as mean � SD for normally distributedvariables and median (25th to 75th percentile) fornon-normally distributed variables, unless otherwisestated. Continuous variables were compared using 1-way analysis of variance and subsequent Bonferronimultiple comparisons test for normally distributeddata and Kruskal-Wallis test followed by Dunn’smultiple comparisons test for non-normally distrib-uted data. Categorical variables were compared usingFisher exact or Pearson chi-square tests as appro-priate. Statistical significance was established atp < 0.05. All data were analyzed using PASW Statis-tics 18 (version 18.0.0, SPSS, Chicago, Illinois).

RESULTS

PATIENT CHARACTERISTICS. Patient characteristicsare shown in Table 1. There was a high prevalence ofstructural heart disease in the cohort, reflecting themore severe spectrum of patients referred to ourinstitution.

ANATOMICAL DISTRIBUTION OF DRIVERS. In total,4,550 re-entrant and 1,017 focal drivers were mapped.The most prominent driver regions were the PVregions: re-entrant drivers were present in region 1 in90%, region 2 in 87%, and 1 or both of these regions in96% of patients, shown in the Central Illustration.Re-entrant drivers were observed specifically at theleft PV antra in 85% of patients, particularly at the leftinferior PV posterior antrum, and the LAA subregionin 55%. The RPV antra harbored re-entrant drivers in87% of patients, with high occurrences at the septalaspects of both the RPVs and the posterior right infe-rior PV antrum. Focal drivers were observed in region1 in 70% (left PVs in 51%, LAA in 50%), region 2 (RPVs)in 31%, and 1 or both regions in 75% of patients. Whenboth re-entrant and focal drivers were included,drivers were located in region 1 in 99%, region 2 in90%, and 1 or both of these regions in 100% of patients.

Other regions were more individually distributed.The inferoposterior LA (region 3) was the nextprominent region that harbored re-entrant drivers(posterior LA 49%, inferior LA 70%, coronary sinusostium 28%), followed by the superior RA (region 4;RA appendage 50%, superolateral RA 46%). Theincreased occurrences of re-entrant drivers in thesefirst 4 regions were also reflected by the number of re-entrant rotations recorded in these regions (OnlineFigure 2). In contrast, fewer re-entrant drivers wereobserved in the inferior RA (region 5, 19%) and roof(region 6, 20%). Figure 2 (and Online Videos 1 and 2)illustrates a re-entrant driver around the RPVs.

DRIVER DISTRIBUTION IN RELATION TO AF DURATION.

Increasing AF duration resulted in increasingly

widespread driver regions. An increase in the pro-portion of patients with re-entrant drivers were seenin the left PV/LAA (p ¼ 0.040), inferoposterior LA(p < 0.001), superior RA (p ¼ 0.026), inferior RA(p ¼ 0.032), and anterior LA/anteroseptal (p ¼ 0.044)regions with increasing AF duration, shown inFigure 3. Differences in proportion of patients withfocal drivers from the superior RA (p ¼ 0.038) andRPV (p ¼ 0.033) regions were observed with pro-gressive AF duration. Figure 4 illustrates the increasein distribution of re-entrant drivers in patients withprogression from the PersSR to Pers<12m andPers>12m groups. A re-entrant driver at the posteriorLA is illustrated in Figure 5 and Online Video 3.

With increasing AF duration, the total number ofre-entrant rotations observed per second significantly

CENTRAL ILLUSTRATION Distribution of Re-Entrant and Focal Drivers in Persistent AF

Lim, H.S. et al. J Am Coll Cardiol. 2017;69(10):1257–69.

(A) Distribution of re-entrant and focal drivers in persistent atrial fibrillation (AF) (n ¼ 105). The asterisk and arrow with circle indicate the percentage of patients with

focal and re-entrant drivers in each region, respectively. (Inset) Regional classification for driver-density maps. See text for details. (B) The number of re-entrant and

focal driver regions increases with increasing AF duration (p < 0.001 between groups). Post hoc analyses: *p < 0.05 Group 3 versus Group 1; *p < 0.05 Group 3 versus

Group 2. (C) The percentage of extra-PV AF termination sites increases with increasing AF duration (p ¼ 0.079). Pers<12m ¼ persistent atrial fibrillation with the

longest episode of continuous AF lasting <12 months; Pers>12m ¼ longstanding persistent atrial fibrillation with continuous atrial fibrillation >12 months; PersSR ¼persistent atrial fibrillation presenting in sinus rhythm; PV ¼ pulmonary vein.

Lim et al. J A C C V O L . 6 9 , N O . 1 0 , 2 0 1 7

Complexity and Distribution of Drivers in Prolonged AF M A R C H 1 4 , 2 0 1 7 : 1 2 5 7 – 6 9

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increased in the extra-PV regions (the value repre-sents the total number of observed re-entrant rota-tions, which may be discontinuous, tallied over therecording period [25th to 75th percentiles]): infer-oposterior LA (0.48 [0 to 1.31] rotations/s for PersSR

vs. 0.69 [0.31 to 1.00] rotations/s for Pers<12m vs. 1.10[0.65 to 1.54] rotations/s for Pers>12m; p ¼ 0.011), su-perior RA (0.23 [0 to 1.11] rotations/s for PersSR vs. 0.55[0 to 1.34] rotations/s for Pers<12m vs. 1.15 [0.48 to1.96] rotations/s for Pers>12m; p ¼ 0.015), and inferior

TABLE 1 Baseline Characteristics

All PatientsPersistent AF

(in SR)Persistent AF<12 Months

Persistent AF>12 Months p Value

N 105 (100.0) 32 (30.5) 45 (42.9) 28 (26.7)

Age, yrs 58.3 � 11.7 58.9 � 11.4 58.4 � 11.9 57.3 � 12.1 0.90

Male 84 (80.0) 25 (78.1) 36 (80.0) 23 (82.1) 0.90

Comorbidities

Congestive heart failure 37 (35.2) 8 (25.0) 19 (42.2) 10 (35.7) 0.30

Hypertension 46 (43.8) 13 (40.6) 21 (46.7) 12 (42.9) 0.90

Diabetes mellitus 11 (10.5) 3 (9.4) 4 (8.9) 4 (14.3) 0.70

Previous stroke/TIA 9 (8.6) 3 (9.4) 2 (4.4) 4 (14.3) 0.30

Structural heart disease 64 (61.0) 18 (56.3) 29 (64.4) 17 (60.7) 0.70

Ischemic 9 (8.6) 5 (15.6) 4 (8.9) 0 (0.0)

Hypertrophic 13 (12.4) 2 (6.3) 6 (13.3) 5 (17.9)

Valvular 6 (5.8) 2 (6.3) 2 (4.4) 2 (7.1)

Idiopathic 34 (32.3) 8 (25.0) 17 (37.8) 9 (32.1)

Other 2 (1.9) 1 (3.1) 0 (0.0) 1 (3.6)

CHADS2 score

0 30 (28.6) 11 (34.4) 11 (24.4) 8 (28.6) 0.90

1 41 (39.0) 12 (37.5) 18 (40.0) 11 (39.3)

$2 34 (32.4) 9 (28.1) 16 (35.6) 9 (32.1)

Mean CHADS2 score 1.2 � 1.1 1.1 � 1.1 1.2 � 1.0 1.3 � 1.2 0.80

AF duration

Diagnosis of AF, months 48 (24–96) 32 (18–95) 60 (22–120) 54 (36–78) 0.30

Maximum duration of continuousAF, months

7 (3–12) 3 (1–7) 6 (2.5–9) 15 (14–21) <0.001

Medications

Previously failed AADs 2.5 � 0.8 2.4 � 0.8 2.6 � 0.8 2.3 � 0.7 0.30

Amiodarone therapy 47 (44.8) 19 (59.4) 20 (44.4) 8 (28.6) 0.10

$1 previous DC cardioversion 83 (79.0) 26 (81.3) 35 (77.8) 22 (78.6) 1.00

Echocardiographic parameters

LA diameter, parasternal view, mm 49.1 � 5.2 47.3 � 5.4 50.3 � 5.1 48.9 � 5.0 0.20

LA size, cm2 26.2 � 5.3 25.1 � 5.8 27.3 � 5.3 25.2 � 4.8 0.20

RA size, cm2 21.2 � 6.3 18.5 � 7.1 21.2 � 5.4 23.3 � 6.6 0.10

LVEF, % 52.3 � 12.9 56.0 � 13.1 50.7 � 13.8 50.6 � 10.2 0.20

Values are n (%), mean � SD, or median (25th to 75th quartile).

AAD ¼ antiarrhythmic drug; AF ¼ atrial fibrillation; CHADS2 ¼ congestive heart failure, hypertension, $75 years of age, diabetes mellitus, and prior stroke or transientischemic attack; DC ¼ direct current; LA ¼ left atrial; LVEF ¼ left ventricular ejection fraction; RA ¼ right atrial; SR ¼ sinus rhythm; TIA ¼ transient ischemic attack.

J A C C V O L . 6 9 , N O . 1 0 , 2 0 1 7 Lim et al.M A R C H 1 4 , 2 0 1 7 : 1 2 5 7 – 6 9 Complexity and Distribution of Drivers in Prolonged AF

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RA (0 [0 to 0] rotations/s for PersSR vs. 0 [0 to 0] ro-tations/s for Pers<12m vs. 0 [0 to 0.38] rotations/s forPers>12m; p ¼ 0.024) (Figures 3C and 3D).

COMPLEXITY OF AF IN RELATION TO AF DURATION.

The complexity of AF patterns increased with longerAF duration (Figure 6). The mean total number ofre-entrant rotations (for all regions) observedincreased with longer AF duration (4.2 � 2.3 rota-tions/s for PersSR vs. 4.5 � 1.9 rotations/s forPers<12m vs. 6.0 � 3.8 rotations/s for Pers>12m;p ¼ 0.027). Similarly, mean total number of re-entrantrotations and focal discharges (for all regions)increased with longer AF duration (5.5 � 2.3 events/sin PersSR vs. 5.6 � 1.8 events/s in Pers<12m vs.7.4 � 4.3 events/s in Pers>12m; p ¼ 0.020).

The number of regions harboring re-entrant driversincreased from a median of 3.5 (interquartile range

[IQR]: 2.0 to 4.8) in PersSR to 4 (IQR: 3 to 5) inPers<12m and 5 (IQR: 4 to 5) in Pers>12m (p < 0.001between groups). The number of foci regionsincreased from 1.5 (IQR: 1 to 2) in PersSR to 2 (IQR: 1 to3) in Pers<12m and 2 (IQR: 1 to 2.75) in Pers>12m(p ¼ 0.032 between groups). A composite sum ofre-entrant and focal driver regions in each patient asan index of overall complexity increased from 4 (IQR:3.25 to 6.0) in PersSR to 6 (IQR: 5 to 7) in Pers<12mand 7 (IQR: 6 to 8) in Pers>12m (p < 0.001 betweengroups).

AF TERMINATION BY DRIVER REGION. ProceduralAF termination was achieved in 73 patients (70%).With targeted driver ablation alone, AF terminationwas observed in 29 (91%) patients in the PersSRgroup, 31 (69%) in the Pers<12m group, and 4 (14%) inthe Pers>12m group (p < 0.001 between groups).

FIGURE 2 Re-Entrant and Focal Drivers in a 55-Year-Old Man With Persistent AF for 3 Months

(A to D) A re-entrant driver is observed to rotate at the right inferior pulmonary vein (RIPV) antrum, gradually meandering toward the carina.

(E) A focal discharge is then observed to arise from the left inferior pulmonary vein (LIPV), initiating 2 wavefronts, (F) 1 of which results in a

transient rotation before dissipating (Online Videos 1 and 2). AF ¼ atrial fibrillation; LSPV ¼ left superior pulmonary vein; RSPV ¼ right superior

pulmonary vein.

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Complexity and Distribution of Drivers in Prolonged AF M A R C H 1 4 , 2 0 1 7 : 1 2 5 7 – 6 9

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Four patients in the Pers<12m group and 5 patients inthe Pers>12m group sustained AF termination duringadditional linear ablation (Online Tables 1 to 3). Sitesof AF termination during driver ablation are depictedin Figure 7A. The last driver region terminating AF isrepresented in Figure 7B. The commonest 2 regionswith AF termination during driver ablation were thePV regions. Other regions include the superior RA(10%), inferoposterior LA (8%), inferior RA (5%), andanterior LA/anteroseptal region (4%). As AF durationincreased, there was a trend toward AF termination atextra-PV sites (p ¼ 0.079) (Central Illustration).Termination of AF in these extra-PV driver regionswere often at a later stage of driver ablation (median 4[IQR: 3 to 4.5] targeted region) and in most casespreceded by driver ablation in 1 or 2 PV regions

(90% of cases). The median number of driver regionsablated for the entire cohort is 4 (IQR: 2 to 6). The AFcycle length prolonged by an average of 10.5 � 8.4 ms,7.3 � 10.3 ms, 5.0 � 11.3 ms, and 2.8 � 5.4 ms afterablation of the first, second, third, and fourth driverregions, respectively.

SPATIOTEMPORAL CHARACTERISTICS OF RE-ENTRANT

DRIVERS. The re-entrant drivers were either singleor multiple and often coexisting. Median number ofre-entrant driver regions was 4 (IQR: 3 to 5). Re-entrant driver activity was periodic but recurred inthe same or adjacent locations. On average 4.8 � 2.7re-entrant rotations were observed per second in thecohort, which increased with longer AF duration(Figure 3). The mean duration of re-entrant drivers

FIGURE 3 Distribution of AF Drivers According to AF Duration

100* *

*

*

*

80

60

40

20

1 2 3 4Regions

Re-entrant

Prop

ortio

n of

Pat

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s (%

)

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*p<0.05

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A

100

PersSR Pers<12m Pers>12m

80

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s (%

)

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*p<0.05

0

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D

(A) Re-entrant driver regions. *p < 0.05, difference between groups. (B) Focal driver regions. *p < 0.05. (C) Number of re-entrant rotations. Median (whiskers: 5th to

95th percentile; boxes: 25th to 75th percentile) shown (C, D). *p < 0.05. (The total number of re-entrant rotations detected per second represents the number of

observed re-entrant rotations, which were intermittent, tallied over the recording period. This value does not reflect the cycle length of the re-entrant driver.) (D)

Number of focal discharges (post hoc analyses in the Online Appendix). AF ¼ atrial fibrillation; Pers<12m ¼ persistent atrial fibrillation with the longest episode of

continuous AF lasting <12 months; Pers>12m ¼ longstanding persistent atrial fibrillation with continuous atrial fibrillation >12 months; PersSR ¼ persistent atrial

fibrillation presenting in sinus rhythm.

J A C C V O L . 6 9 , N O . 1 0 , 2 0 1 7 Lim et al.M A R C H 1 4 , 2 0 1 7 : 1 2 5 7 – 6 9 Complexity and Distribution of Drivers in Prolonged AF

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was 458 � 90 ms, and mean number of uninterruptedrotations was 2.9 � 0.3. The re-entrant drivers werealso observed to meander, and the mean ratio of theaxes of re-entrant driver trajectories, calculated as theratio of the distance of the major axis over the minoraxis of each re-entrant driver trajectory, was 2.14 �0.29. The core of the re-entrant drivers was observedto meander variably over an area of 7.3 � 2.2 cm2.

DISCUSSION

MAJOR FINDINGS. To our knowledge, the presentstudy is the largest study to date to examine AF

drivers in relation to AF duration in a consecutive andhomogenous cohort of PsAF patients undergoing denovo ablation. The main findings are summarized asthe following:

1. The complexity of AF drivers increases with longerAF duration, evidenced by increased total numberof re-entrant rotations, total number of re-entrantrotations and focal discharges, number of regionsharboring re-entrant drivers, and number ofregions harboring re-entrant and focal drivers.

2. The PV regions remain the predominant driverregions in PsAF.

FIGURE 4 Aggregated Driver-Density Maps in 3 Patients With Varying AF Durations

Re-entrant driver distribution on aggregated driver-density maps in 3 patients with (A) PersSR versus (B) Pers<12m versus (C) Pers>12m.

Posteroanterior (left panels) and anteroposterior (right panels) views are displayed. Blue is the background color of the biatrial geometry.

Green, yellow, and red colors highlight clusters of re-entrant drivers at increasing density. Re-entrant driver regions became increasingly

widespread with AF progression. MA ¼ mitral annulus; TA ¼ tricuspid annulus; other abbreviations as in Figures 2 and 3.

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3. With increasing AF duration, regions adjacent tothe PVs and extra-PV regions are involved, spe-cifically the inferoposterior LA, the anteriorLA/septal region, and the RA.

4. Ablation targeting these driver regions resulted inAF termination in 70% of patients, indicating therole of these drivers in sustaining AF. However, asharp decline in termination of the arrhythmia isnoted in longstanding PsAF (>12 months duration).

DISTRIBUTION OF DRIVERS IN HUMAN PERSISTENT

AF: IMPORTANCE OF PV ANTRAL REGIONS. Thepresent study using noninvasive mapping demon-strated that the PV antral regions were the mostprevalent regions for driver activity. This corroborates

with previous animal and human studies withdifferent mapping approaches (6,13–15). Animalstudies in isolated sheep hearts have demonstratedthat the region surrounding the PV ostium had thehighest dominant frequency (DF) in the majority of AFepisodes (6). Furthermore, the PV-LA junction is foundto be a recurrent rotor-anchoring site in Langendorff-perfused canine heart preparations (13). Humanstudies on DF sites have found a clustering of DF sitesaround the PV regions for paroxysmal AF, but atrial DFsites were more prevalent in permanent AF (8). Whatpredisposes the PV regions to be dominant driver re-gions? Rotors are known to anchor at barriers such asanatomical structures, fibrosis, and functional areas ofconduction heterogeneity and differences in

FIGURE 5 Re-Entrant Driver in a 75-Year-Old Man With Persistent AF for 4 Months

A re-entrant driver is observed to rotate counterclockwise at the midposterior left atrial (LA) wall (A to F), gradually drifting toward the

inferior LA (Online Video 3). Abbreviations as in Figure 2.

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refractoriness (16). Complex fiber orientation at the PVantra and unique electrophysiological characteristicsin the PVs account for its arrhythmogenicity and pro-motes re-entry (17). The close proximity to the PVtriggers may result in atrial electrical remodeling fromrepetitive focal discharges, analogous to rapid atrialpacing (3). Computer modeling of morphologicallyaccurate atria has indicated the PV region to be apreferential site for rotor anchoring (8). Finally,ganglionated plexi are also situated in the PV antralregion.

INCREASING COMPLEXITY AND DISTRIBUTION OF

AF DRIVERS WITH PROLONGED AF DURATION. Thecomplexity of AF drivers increased with longer AFduration in this study, evidenced by increased numberof re-entrant rotations and number of re-entrant rota-tions and foci. This corroborates findings from studies

utilizing activation mapping of increased number ofwavelets and focal sites in longstanding PsAF (12). Ahigh proportion of LAA and RA appendage fociaccounted for the increase in focal drivers in regions 1and 4, respectively, with increasing AF duration. In theRPV region, however, focal drivers subsequentlydecreased in the PersAF>12m group, perhaps indica-tive of a transition from a PV trigger-based disease to amore substrate-based or extra-PV–based pathologywith longstanding PsAF (18).

With longer AF duration, driver regions becameincreasingly widespread, particularly in areas adja-cent to the PVs such as the posterior and inferior LAor coronary sinus, LAA, and other areas such as theRA and anterior LA/septal region. The significance ofthe posterior LA wall in harboring re-entrant driversin this study confirms findings from previous animaland human studies (10,15,19). In experimental sheep

FIGURE 6 Complexity of AF Drivers According to AF Duration

Pers>12m * *

Pers<12m

PersSR

0

p=0.027

5Total No. of Re-entrant Rotations

(per second)

Total No. of Re-entrant Rotations

10 15

A

Pers>12m *

Pers<12m

PersSR

1

p<O.OO1

3 42No. of Regions

No. of Re-entrant Driver Regions

5 6 7

D

Pers>12m

*Pers<12m

PersSR

1

p=O.032

3 42No. of Regions

No. of Focal Driver Regions

5 6 7

E

Pers>12m

Pers<12m

PersSR

1

p=0.7

2 3Total No. of Focal Events

(per second)

Total No. of Focal Events

4 5

B

Pers>12m

Pers<12m

PersSR

0

p=0.020

5Total No. of Re-entrant Rotations and Focal

Events (per second)

Total No. of Re-entrant Rotationsand Focal Events

10 15

C

(A) Total number of re-entrant rotations. p ¼ 0.027 between groups. Mean � SD shown (A to C). (B) Total number of focal discharges. p ¼ 0.7 between groups. (C)

Total number of re-entrant rotations and focal discharges. p ¼ 0.020 between groups. (D) Re-entrant driver regions. p < 0.001 between groups. Median and range

shown (D, E). (E) Focal driver regions. p ¼ 0.032 between groups. Post hoc analyses are available in the Online Appendix. Abbreviations as in Figure 2.

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studies of stable AF, the posterior LA was found toharbor fast and highly organized activity (6,19). Theregion inferior to the PV ostium was found to be thenext commonest region of highest DF for AF episodesafter the PV ostia and PV ostia/LAA groove in anotherstudy (6). The posterior and inferior LA is prone toabnormal conduction abnormalities and atrial fibrosis(20), whereby the complex regional histoanatomicalarchitecture provides a substrate for sink-sourcemismatch and re-entry formation. With surgicalelectrical isolation of the PV region including theposterior wall, AF was no longer inducible in otherparts of the atria (15). Two previous studies havehighlighted the arrhythmogenic role of the superiorRA as revealed in this study, suggesting both re-entrant and focal activity as underlying mechanisms(14,21). Re-entry in the RA is attributed to annexedanatomical structures such as the RA appendage,crista terminalis, and pectinate bundles; however, inother cases a functional determinant has also beenimplicated (5,21).

SPATIOTEMPORAL CHARACTERISTICS OF RE-ENTRANT

DRIVERS. In this study, re-entrant drivers were

observed to be periodic and meandering in nature.The meandering nature observed in this study isconsistent with previous animal studies and simula-tion models of human atrial tissue (4,22). Periodicityin AF drivers has been described in animal and hu-man studies (4–6,19,23). Skanes et al. (5) demon-strated multiple coexisting discrete sources (1 to 3)during AF in Langendorff-perfused sheep hearts, andperiodic activation consisting of 4 to 14 consecutiveactivations (5). The phenomenon of coexistent mul-tiple re-entrant circuits, whereby some re-entrantcircuits would disappear while others reform, sothat at least 1 to 4 re-entrant circuits were alwayspresent, was described in canine AF-models by Ryuet al. (4). In humans with mainly PsAF, Ghoraani et al.(23) recorded rotational activation (average 3 sites perpatient) using a multielectrode catheter, the majorityof which were nonsustained (<1 s). The observation ofAF termination with ablation of the driver regionsand progressive AF cycle length prolongation withablation of each successive driver region support anactive role of these AF drivers. However, the inter-mittent and periodic nature of the focal and re-entrant events suggests that AF is maintained by

FIGURE 7 Sites of AF Termination

15%

18%

8%

10%5%

9%

30%

1%4% No Term

1 LPV/LAA2 RPV/posterior septum3 Inferoposterior LA/CS4 Superior RA5 Inferior RA6 Anterior LA/Roof7 Anterior LA/septumLinear

A

B

(A) Sites of AF termination (red dots) by driver ablation alone. (B) AF termination by driver region. AP ¼ anteroposterior view; CS ¼ coronary sinus; LAA ¼ left atrial

appendage; LPV ¼ left pulmonary vein; PA ¼ posteroanterior view; RA ¼ right atrium; RPV ¼ right pulmonary vein; other abbreviations as in Figures 2 and 4.

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intermittent but recurrently firing or occurring sour-ces generated from multiple sites (median 4 regionsin this study). Smaller or secondary wavefront activ-ity that may contribute to AF maintenance couldnot be evaluated by the current mapping system.In addition, the definition used in the current study of2 consecutive focal or spatially stable re-entrantevents increased the specificity but may havedecreased the sensitivity of detecting these events,whereby single firing or unstable re-entry may alsocontribute to AF maintenance.

CLINICAL IMPLICATIONS. First, the finding that thecomplexity of AF patterns increases particularly inPers>12m, coupled with a sharp decline in AF termi-nation rates underscores the importance of earlyintervention in the management of AF, whethermedical or invasive. Second, current catheter-basedand surgical therapy for PsAF is diverse. The currentstudy indicates regions that are highly arrhythmo-genic include the PV antral regions and the infer-oposterior wall. This may explain the high success

rates for procedures that involve PV antral isolationand posterior wall isolation (15,24). In PsAF of longerduration, extra-PV drivers become more individual-ized but regions such as the inferoposterior LA wall orcoronary sinus, RA, and anterior LA/septal areasshould be considered. In this setting, panoramicelectrical mapping may be combined with substrateimaging (e.g., delayed enhancement magnetic reso-nance imaging) to determine the interaction with theunderlying atrial substrate. Third, a high proceduralsuccess rate with driver ablation alone was noted inthe PersSR group. These findings imply that restora-tion of sinus rhythm, if achievable, prior to catheter-based interventions may aid with reverse electricalremodeling. Finally, ablation directed at AF driversites minimizes the extent of radiofrequency delivery(9,11); however, the optimum ablation strategy forsuch approaches warrants further study.

STUDY LIMITATIONS. First, due to the close prox-imity of overlapping structures, specific areas,particularly the interatrial septum, PV/LAA ridge,

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE:

Drivers of AF, located predominantly in or adjacent to

the PV antra, become more widely distributed and

complex as duration of AF increases.

TRANSLATIONAL OUTLOOK: Further studies are

required to identify patients who gain the most

benefit from targeting drivers beyond the PVs during

ablation of AF.

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and inferior LA or coronary sinus are difficult todelineate (11,12). Second, the transformation of datato phase-based analysis may detect nonphysiologicalartifacts due to incomplete wave curvatures duringlocal phase progression. Third, although multiplewindows with long R-R intervals were recorded,there is the possibility that further windows maydetect more drivers elsewhere. To minimize theselimitations, each body surface electrode wasscreened for signal quality, and re-entrant activitywas defined as $2 fully rotated waves and verifiedby local unipolar electrograms. Fourth, this studyexamined localized AF drivers using noninvasivemapping and phase-based algorithms. Other lessstable or complex wavefront activity and the in-teractions between localized driver activity andother potential mechanisms in AF and the underly-ing individual atrial substrate were not analyzed inthe study. Fifth, further validation studies arerequired with this mapping technique. However,a multicenter European study provided similarresults (25).

CONCLUSIONS

In this study of PsAF patients undergoing de novoablation, the complexity of AF drivers was observed

to increase with prolonged AF duration. Re-entrantand focal drivers were predominantly located in thePV antral regions and adjacent inferoposterior LAwall. However, with longer AF duration, multipledrivers were located at extra-PV sites. A sharp declinein AF termination rate was noted in patients withlongstanding PsAF, underscoring the importance ofearly intervention.

ADDRESS FOR CORRESPONDENCE: Dr. MichelHaïssaguerre, Hôpital Cardiologique du Haut-Lévêque,Avenue de Magellan, 33604 Bordeaux-Pessac, France.E-mail: michel.haissaguerre@chu-bordeaux.fr.

RE F E RENCE S

1. Moe GK. On the multiple wavelet hypothesis ofatrial fibrillation. Arch Int Pharmacodyn Ther 1962;140:183–8.

2. Allessie MA, Lammers WJEP, Bonke FIM,Hollen J. Experimental evaluation of Moe’s mul-tiple wavelet hypothesis of atrial fibrillation. In:Zipes DP, Jalife J, editors. Cardiac Arrhythmias.New York, NY: Grune & Stratton, 1985:265–75.

3. Haïssaguerre M, Jaïs P, Shah DC, et al. Sponta-neous initiation of atrial fibrillation by ectopicbeats originating in the pulmonary veins. N Engl JMed 1998;339:659–66.

4. Ryu K, Sahadevan J, Khrestian CM,Stambler BS, Waldo AL. Use of fast fouriertransform analysis of atrial electrograms for rapidcharacterization of atrial activation-implicationsfor delineating possible mechanisms of atrialtachyarrhythmias. J Cardiovasc Electrophysiol2006;17:198–206.

5. Skanes AC, Mandapati R, Berenfeld O,Davidenko JM, Jalife J. Spatiotemporal periodicityduring atrial fibrillation in the isolated sheep heart.Circulation 1998;98:1236–48.

6. Mandapati R, Skanes A, Chen J, Berenfeld O,Jalife J. Stable microre-entrant sources as amechanism of atrial fibrillation in the isolatedsheep heart. Circulation 2000;101:194–9.

7. Haïssaguerre M, Hocini M, Sanders P, et al.Localized sources maintaining atrial fibrillationorganized by prior ablation. Circulation 2006;113:616–25.

8. Sanders P, Berenfeld O, Hocini M, et al. Spectralanalysis identifies sites of high-frequency activitymaintaining atrial fibrillation in humans. Circula-tion 2005;112:789–97.

9. Narayan SM, Krummen DE, Shivkumar K,Clopton P, Rappel WJ, Miller JM. Treatment ofatrial fibrillation by the ablation of localizedsources: CONFIRM (Conventional Ablation forAtrial Fibrillation With or Without Focal Impulseand Rotor Modulation) trial. J Am Coll Cardiol2012;60:628–36.

10. Sahadevan J, Ryu K, Peltz L, et al. Epicardialmapping of chronic atrial fibrillation in patients:preliminary observations. Circulation 2004;110:3293–9.

11. Haïssaguerre M, Hocini M, Denis A, et al. Driverdomains in persistent atrial fibrillation. Circulation2014;130:530–8.

12. Cuculich PS, Wang Y, Lindsay BD, et al.Noninvasive characterization of epicardialactivation in humans with diverse atrialfibrillation patterns. Circulation 2010;122:1364–72.

13. Chou CC, Chang PC, Wen MS, et al. Epicardialablation of rotors suppresses inducibility ofacetylcholine-induced atrial fibrillation in left pulmo-nary vein-left atrium preparations in a beagle heartfailure model. J Am Coll Cardiol 2011;58:158–66.

14. Ryu K, Shroff SC, Sahadevan J, Martovitz NL,Khrestian CM, Stambler BS. Mapping of atrialactivation during sustained atrial fibrillation indogs with rapid ventricular pacing induced heartfailure: evidence for a role of driver regions.J Cardiovasc Electrophysiol 2005;16:1348–58.

15. Todd DM, Skanes AC, Guiraudon G, et al. Roleof the posterior left atrium and pulmonary veins inhuman lone atrial fibrillation: electrophysiologicaland pathological data from patients undergoingatrial fibrillation surgery. Circulation 2003;108:3108–14.

16. Comtois P, Kneller J, Nattel S. Of circles andspirals: bridging the gap between the leading cir-cle and spiral wave concepts of cardiac reentry.Europace 2005;7 Suppl 2:10–20.

17. Hocini M, Ho SY, Kawara T, et al. Electricalconduction in canine pulmonary veins: electro-physiological and anatomic correlation. Circulation2002;105:2442–8.

18. Kurotobi T, Iwakura K, Inoue K, et al.Multiple arrhythmogenic foci associated with

J A C C V O L . 6 9 , N O . 1 0 , 2 0 1 7 Lim et al.M A R C H 1 4 , 2 0 1 7 : 1 2 5 7 – 6 9 Complexity and Distribution of Drivers in Prolonged AF

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the development of perpetuation of atrialfibrillation. Circ Arrhythm Electrophysiol 2010;3:39–45.

19. Kalifa J, Tanaka K, Zaitsev AV, et al. Mecha-nisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium ofthe isolated sheep heart during atrial fibrillation.Circulation 2006;113:626–33.

20. Martins RP, Kaur K, Hwang E, et al.Dominant frequency increase rate predictstransition from paroxysmal to long-term persis-tent atrial fibrillation. Circulation 2014;129:1472–82.

21. Atienza F, Almendral J,Moreno J, et al. Activationof inward rectifier potassium channels accelerates

atrial fibrillation in humans: evidence for a re-entrantmechanism. Circulation 2006;114:2434–42.

22. Zlochiver S, Yamazaki M, Kalifa J, Berenfeld O.Rotor meandering contributes to irregularity inelectrograms during atrial fibrillation. HeartRhythm 2008;5:846–54.

23. Ghoraani B, Dalvi R, Gizurarson S, et al.Localized rotational activation in the leftatrium during human atrial fibrillation: relationshipto complex fractionated atrial electrograms andlow-voltage zones. Heart Rhythm 2013;10:1830–8.

24. Verma A, Jiang CY, Betts TR, et al. Approachesto catheter ablation for persistent atrial fibrilla-tion. N Engl J Med 2015;372:1812–22.

25. Knecht S, Sohal M, Arentz T, et al. Noninvasivemapping prior to ablation for persistent atrialfibrillation: The AFACART multicenter study.Europace 2017 [in press].

KEY WORDS complexity, drivers,panoramic mapping, persistent atrialfibrillation

APPENDIX For expanded Methods,Results, and References sections as well assupplemental tables, figures, and videos,please see the online version of this article.