Impact of Stepwise Ablation on the Bi-Atrial Substrate in...

DOI: 10.1161/CIRCEP.113.000390

1

Impact of Stepwise Ablation on the Bi-Atrial Substrate in Patients with

Persistent Atrial Fibrillation and Heart Failure

Running title: Jones et al.; Ablation in Persistent AF and Heart Failure

David G. Jones, MD(Res); Shouvik K. Haldar, MBBS; Julian W.E. Jarman, MD(Res);

Sofian Johar, PhD; Wajid Hussain, MBChB; Vias Markides, MD; Tom Wong, MD

Heart Rhythm Centre and NIHR Cardiovascular Biomedical Research Unit, Royal Brompton &

Harefield NHS Foundation Trust, Imperial College London, London, United Kingdom

Corresponding author:

Tom Wong, MD

Royal Brompton Hospital

Sydney Street

London SW3 6NP

United Kingdom

Tel:+442073518619

Fax:+442073518634

E-mail: [email protected]

Journal Subject Codes: [22] Ablation/ICD/surgery, [110] Congestive, [106] Electrophysiology, [5] Arrhythmias, clinical electrophysiology, drugs

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DOI: 10.1161/CIRCEP.113.000390

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Abstract

Background - Ablation of persistent atrial fibrillation (AF) can be challenging, often involving

not only pulmonary vein isolation (PVI) but also additional linear lesions and ablation of

complex fractionated electrograms (CFE). We examined the impact of stepwise ablation on a

human model of advanced atrial substrate, persistent AF in heart failure.

Methods and Results - In 30 patients with persistent AF and left ventricular ejection fraction

35%, high-density CFE maps were recorded biatrially at baseline, in the left atrium (LA) after

PVI and linear lesions (roof and mitral isthmus), and biatrially after LA-CFE ablation. Surface

area of CFE (mean cycle length 120ms) remote to PVI and linear lesions, defined as CFE-area,

was reduced after PVI(18.3±12.03cm2 to 10.2±7.1cm2;p<0.001), and again after linear lesions

(7.7±6.5cm2;p=0.006). Complete mitral isthmus block predicted greater CFE reduction (p=0.02).

Right atrial CFE-area was reduced by LA ablation, from 25.9±14.1 to 12.9±11.8cm2(p<0.001).

Estimated 1-year arrhythmia-free survival was 72% after a single procedure. Incomplete linear

lesion block was an independent predictor of arrhythmia recurrence(HR 4.69, 95% CI 1.05-

21.06;p=0.04).

Conclusions - Remote LA-CFE-area was progressively reduced following PVI and linear lesions,

and LA ablation reduced right atrial CFE-area. Reduction of CFE-area at sites remote from

ablation would suggest either regression of the advanced atrial substrate or that these CFE were

functional phenomena. Nevertheless, in an advanced AF substrate, linear lesions after PVI

diminished the target area for CFE ablation and complete lesions resulted in a favourable clinical

outcome.

Key words: atrial fibrillation, heart failure, mapping, ablation, complex fractionated electrograms

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Catheter ablation of paroxysmal atrial fibrillation (AF) via pulmonary vein isolation (PVI) is

highly effective.1,2 In contrast, in the majority of those with persistent AF, particularly if

longstanding or associated with structural heart disease, PVI is crucial but alone is often

insufficient for long-term maintenance of sinus rhythm. Ablation of complex fractionated

electrograms (CFE), which may contribute towards – or reflect severity of – the atrial substrate,3

has shown variable benefit in randomized studies.4,5 Linear lesions at the left atrial roof and

lateral mitral isthmus can also improve outcomes.6,7 Combining these approaches appears

beneficial,8 although the optimal ablation strategies and order of their application remain

uncertain.

In patients with structurally normal hearts, PVI reduces remote left atrial CFE.9,10

Experimental and clinical models suggest that, unlike the reversible electrical remodelling

associated with atrial tachymyopathy or ‘lone’ AF, where remote CFE reduction might be

explained by acute electrical remodelling, a more advanced atrial substrate is seen in heart failure

with evidence of structural remodelling, including dilatation and fibrosis which are not acutely

reversible.11,12 In the latter population, the effect of PVI and linear lesions on CFE remote from

ablation sites is not known.

We sought to investigate the biatrial impact of stepwise ablation on CFE in patients with

the advanced atrial substrate of persistent AF and heart failure, and to assess factors influencing

clinical outcome of catheter ablation in this challenging population.

Methods

Patient population

Patients were recruited from the Ablation versus Rate Control for persistent atrial fibrillation in

Heart Failure (ARC-HF) trial (ClinicalTrials.gov, NCT00878384).13 All had symptomatic

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persistent AF, without prior ablation, and left ventricular ejection fraction . All patients

gave written informed consent for the study, which was approved by the local clinical research-

ethics committee.

Electrophysiology procedure

Procedures were performed on continuous oral anticoagulation (bridging low-molecular-weight

heparin pre-2011). Under general anaesthesia, transesophageal echocardiography ruled out

intracardiac thrombus and guided transseptal puncture. Patients were heparinized to

ACT>300seconds. The following catheters were inserted femorally: (i) decapole(CR Bard,

Lowell, MA) to distal coronary sinus(CS); (ii) decapole to right atrial appendage(RAA); (iii) 20-

pole high-density mapping catheter(AFocusII, St Jude Medical, St Paul, MN) via long

sheaths(Preface, Biosense Webster, Diamond Bar, CA) to right atrium(RA) and left atrium(LA)

sequentially; (iv) 3.5mm irrigated-tip catheter (Thermocool, Biosense Webster) for ablation,

power limit 35W-anterior LA, 30W-posterior LA, 25W-CS, and 40W-cavotricuspid

isthmus(CTI). The NavX system(version8, St Jude Medical) was used with the high-density

catheter to create biatrial geometry.

Complex fractionated electrogram mapping

High-frequency atrial potentials exhibiting multiple deflections from the isoelectric line were

characterized using the NavX CFE-mean tool. CFE-mean is defined as the mean time between

consecutive deflections during a pre-defined recording period, and has been previously described

in detail.14 CFE were defined as sites with CFE-mean 120ms, using a 5-second recording

duration.14,15 Signals were recorded from all 19 bipoles of the roving high-density catheter. CFE-

mean tool settings were: electrogram width<10ms (to remove far-field signals), refractory period

30ms (values below this being regarded as non-physiologic for local re-activation), interpolation

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and surface projection<10mm based on previous studies.14,15 Voltage-detection threshold was

adjusted to exclude background noise and avoid false-positive CFE annotation, and fixed for

subsequent maps. Points>10mm from the surface, and those displaying electrical interference,

were deleted. Scar was defined as<0.05mV. Acquisitions were made until the whole

endocardial surface was covered. The mitral/tricuspid annuli were defined by typical

electrograms and the contained area excluded.

Sequential atrial CFE maps were performed (i) at baseline(RA/LA), (ii) after PVI(LA

only), (iii) after roof- and mitral-lines(LA only), and (iv) after LA-CFE ablation (RA/LA)

(Figure 1). RAA and left atrial appendage(LAA) cycle length(CL) was recorded at each stage.

Catheter ablation protocol

Antral PVI was performed in ipsilateral pairs, with carina ablation when necessary, and re-

isolation performed if required prior to all subsequent CFE maps. Linear ablation was performed

at the roof between the venous isolation lines, and at the lateral mitral isthmus between the left

inferior pulmonary vein and the mitral valve annulus. The subsequent LA-CFE map was used to

guide ablation of CFE, with an endpoint of organisation/abolition of local electrograms at all

CFE sites except at the LAA (avoided to prevent inadvertent isolation). If AF persisted, DC

cardioversion was performed after final CFE maps. If atrial tachycardia occurred, the protocol

was terminated and the tachycardia mapped and ablated. In sinus rhythm, PVI was reassessed

and re-ablated if necessary with the endpoint of entrance block. Bidirectional mitral- and roof-

line block was assessed by differential pacing from the LAA, CS and posterior wall: the presence

of a blocked line immediately after cardioversion was defined as primary block. Further ablation

was performed at incomplete lines, and then at the CTI, to achieve bidirectional block.

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Analysis of CFE maps

Each map was analysed for CFE coverage. Using the surface-marker function, all contiguous

zones of CFE were annotated, and the areas enclosed defined as CFE-area. All LA-CFE maps

were superimposed on the geometry recorded immediately after linear lesions(Figure 2). The

denominator LA area excluded the PVI encirclements and 5mm from PVI and linear lesions,

aiming to assess the effect of these lesions only on remote CFE. The final (post-CFE ablation)

map assessed direct impact of ablation on residual LA-CFE. In order to assess the remote effect

of ablation on the RA, the RA-CFE maps were superimposed upon the final RA geometry: any

LA ablation lesions within 10mm of the RA surface were projected and these areas excluded to

minimize confounding impact of transmural LA lesions(Figure 3).

In order to categorize CFE distribution, the LA was divided into 3 segments as described

elsewhere,16 namely anterior, posterior (each defined by a superior limit of the roof-line, and

lateral limit of the mitral isthmus line), and appendage(Figure 4a). The RA was similarly

segmented into lateral, septal (split at the mid-line of the tricuspid annulus), and

appendage(Figure 4b).

Statistical analysis

Continuous data are presented as mean±standard deviation, and categorical data as

frequency/percentage. Median/interquartile range is also presented for baseline variables and

non-normally distributed data. CFE-area was analysed by absolute and percentage coverage of

atrial surface. To account for multiple measurements, regression with robust variances was

performed using individual patients as a cluster variable, allowing relaxing of the assumption of

independence within clusters. Stepwise change in CFE-area and CL was analysed by paired t-

test, using a Bonferroni correction to account for multiple comparisons. Linear regression was

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performed to assess factors associated with baseline CFE-area (age, gender, AFCL, heart failure

aetiology, amiodarone, LA diameter, AF-duration, and LVEF), reduction of remote RA-CFE

area (adding RF-duration), reduction of remote LA-CFE area by PVI and linear lesions (adding

primary linear block). Logistic regression was performed to assess predictors of AF termination.

Pearson correlations were performed between changes in CL and CFE. Arrhythmia-free survival

was assessed by Kaplan-Meier technique, and Cox-regression used to assess influencing factors.

Analysis was performed within Stata for Windows. Two-sided P-values<0.05 were regarded as

significant.

Follow-up

All antiarrhythmics except non-sotalol beta-blockers were discontinued post-ablation, unless

indicated for ventricular arrhythmia. Patients were followed up at 3, 6, and 12 months, routinely

6-monthly thereafter, and additionally for symptomatic recurrence. 48h-Holter recordings, and

device interrogation where possible, were performed at 6 and 12 months, and ECG at subsequent

follow-ups. Arrhythmia recurrence was defined as documented AF or atrial tachycardia

>30seconds after a 2-month blanking period.

Results

A total of 30 patients were studied, comprising consecutive patients from the ablation arm of the

ARC-HF study13(n=24; a 25th with incomplete mapping data was excluded) and those originally

allocated to rate-control who subsequently underwent ablation after completing trial follow-

up(n=6). Baseline patient characteristics are summarized in Table 1. Heart failure aetiology

was ischaemic in 12 patients(40%), with 3 post-viral, 1 familial, 1 post-alcohol, and the

remainder idiopathic. 11 patients had mild mitral regurgitation, 4 mild-moderate, and none

severe.

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Catheter ablation procedure

Total procedural duration was 331±55 min, fluoroscopy time 79±18min, and total

radiofrequency ablation time pre-cardioversion was 82±19min(PVI 46±17min; roof 3.3±1.7min,

mitral isthmus 4.0±2.3min, CFE 12.1±7.7min). Post-cardioversion, primary roof-block was

present in 26/30, the remaining 4 being blocked after further ablation(2.3±1.4min). There was

primary mitral-block in 11/30 patients, and further ablation(6.6±3.5min) in the remainder

(including epicardially via the coronary sinus in 15) achieved block in 28/30(93%). CTI

ablation(8.8±4.4min) was performed in 28/30 patients, achieving bidirectional block in

27/28(96%).

Atrial fibrillation termination

Termination of AF was observed in 6 cases. In 2 this occurred just prior to CFE ablation: roof-

dependent atrial tachycardias were mapped and ablated to sinus rhythm. In 4, AF-termination

occurred during CFE ablation, 2 into sustained atrial tachycardia (peri-mitral and focal – both

successfully ablated), and 2 via transient organisation then sinus rhythm. Considering baseline

CL, overall CL prolongation prior to termination, CFE-area, LA size, primary linear lesion block,

RF time, age, and AF history, there were no identifiable predictors of AF-termination.

Mapping procedure

A total of 168 CFE maps were acquired(Figure 1), constituting 114 LA maps(479±99

points/map) and 54 RA maps(373±96 points/map). The number of points per map did not differ

significantly between baseline and subsequent LA(p=0.18) and RA(p=0.89) maps. Adjusted

voltage-detection threshold was 0.097±0.029mV. The total surface-area included for sequential

CFE-area analysis was 117±24cm2 in the LA(total LA surface 213±43cm2, 96±25cm2 excluded

by PVI/linear lesions) and 136±33cm2 in the RA. Total LA-CFE area, before exclusion of

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PVI/linear lesion zones, was 20.4±12.3cm2.

Impact of catheter ablation on CFE-area

At baseline LA-CFE-area was 18.3±12.0cm2(16.2±10.6% of the analysed LA surface)

comprising 7.9±6.0cm2(6.8±5.1%) anteriorly, 6.6±5.8cm2(5.9±5.3%) posteriorly, and

3.8±4.1cm2(3.5±3.8%) in the LAA. After PVI there was a reduction in CFE-area to

10.2±7.1cm2(9.0±6.6%;p<0.001 versus baseline), comprising 4.5±4.0cm2(3.8±3.2%; p<0.001)

anteriorly, 2.8±3.2cm2(2.6±3.0%;p<0.001) posteriorly, and 2.8±2.5cm2(2.5±2.3%;p=0.32) in the

LAA. After addition of linear lesions and compared with post-PVI analysis, total LA-CFE-area

had further reduced to 7.7±6.5cm2 (6.9±5.9%;p=0.006), comprising

4.2±4.2cm2(3.7±3.7%;p=1.0) anteriorly, 1.7±2.8cm2(1.6±2.6%;p=0.02) posteriorly, and

1.7±1.8cm2(1.6±1.7%;p=0.04) in the LAA (Figure 5a).

As expected, direct CFE ablation significantly reduced final LA-CFE-area, compared

with post-linear ablation analysis, to 3.1±3.5cm2(2.8±3.0%;p=0.002), comprising

1.4±2.0cm2(1.1±1.6%;p<0.001) anteriorly, 0.2±0.9cm2(0.2±0.8%;p=0.01) posteriorly, and

1.6±2.1cm2(1.5±2.1%;p=1.0) in the LAA.

At baseline, RA-CFE-area was 25.9±14.1cm2(19.2±10.3% of the total RA surface),

comprising 9.6±6.8cm2(7.2±4.9%) laterally, 10.1±7.2cm2(7.7±5.9%) septally, and

6.2±5.8cm2(4.3±3.8%) in RAA. Final RA-CFE-area after LA ablation was reduced to

12.9±11.8cm2(9.9±7.8%;p<0.001), comprising 7.0±7.1cm2(5.6±5.3%;p=0.03) laterally,

2.5±2.8cm2(2.0±2.1%;p<0.001) septally, and 3.6±3.9cm2(2.5±2.6%; p=0.01) in the RAA (Figure

5b).

Impact of catheter ablation on AF cycle-length

Analysing all 3 components of ablation, LAA CL prolonged by 5.9ms (95%CI 3.4 to 8.4,

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p<0.001) and RAA CL by 3.2ms (95%CI 0.6 to 5.8, p=0.02) per step. LAA CL at baseline was

161±28ms, prolonging to 170±37ms after PVI(p=0.01), 174±34ms after linear ablation(p=0.46

versus post-PVI), and 180±42ms after CFE ablation(p=0.04 versus post-linear). RAA CL was

lengthened from 167±33ms at baseline to 175±33ms after PVI(p=0.02), remained 174±30ms

after linear ablation (p=0.88 versus post-PVI), and prolonged to 179±41ms after CFE

ablation(p=0.03 versus post-linear). Hence bi-atrial CL prolonged significantly after PVI and

CFE ablation, but was not impacted independently by linear ablation. Change in CL did not

significantly correlate with change in CFE-area(R=0.21 in RA, p=0.35, for sequential LA maps

R=0.08-0.29, p=0.12-0.91).

Predictors of baseline CFE-area

In multivariable analysis only non-ischaemic aetiology was a risk factor for higher baseline RA

percentage CFE-area(p=0.002, coefficient 11.2cm2,95%CI 4.5 to 17.9). Higher LA percentage

CFE-area was only associated with shorter LAA CL(p=0.03, coefficient -0.084, 95%CI -0.161 to

-0.008).

Predictors of CFE-area reduction after PVI and linear lesions

After correction for baseline remote CFE-area, the reduction in CFE by PVI was independent of

any identifiable variable. The reduction in CFE after linear lesions was greater in those with

primary mitral-block(p=0.02, coefficient -2.75cm2, 95%CI -5.13 to -0.39); primary roof-block

had no significant influence(p=0.17).

Clinical outcome

After a single ablation procedure, at 494±223days follow-up, 19/30 patients(63%) were free of

atrial arrhythmias. Of the 11 patients with recurrence, 3 had AF and 8 had atrial tachycardia.

Arrhythmia-free survival was 71.8%(95%CI 51.3 to 84.8%) at 1 year, off antiarrhythmic drugs,

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after a single procedure. The presence of unblocked linear lesions was the only predictor of

arrhythmia recurrence in multivariable analysis(table 2). No patient with procedural AF

termination had recurrence within the follow-up period. Three patients died of progressive heart

failure during follow-up at 1, 11 and 14 months: none had documented recurrent atrial

arrhythmia.

Discussion

The main finding of this study is that, in this human model of advanced atrial substrate –

persistent AF and heart failure – left atrial CFE-area was progressively reduced at remote sites

following PVI and linear ablation. Furthermore, right atrial CFE-area was reduced after ablation

confined to the LA. In the LA, complete mitral isthmus block produced greater reduction of

CFE-area compared with incomplete block, and map-guided ablation of residual (non-LAA)

CFE after PVI and linear lesions eliminated the majority of CFE. The stepwise ablation strategy

resulted in a high freedom from atrial arrhythmia following a single procedure, with atrial

tachycardia the usual mode of recurrence. The presence of unblocked linear lesions at the end of

the index procedure was the only independent predictor of arrhythmia recurrence.

Ablation of complex fractionated electrograms

Since the initial data supporting CFE ablation to eradicate AF,3 investigators have targeted CFE

alone, with PVI, or within stepwise strategies. However, randomized studies have produced

conflicting results.4,5,17 In one, algorithm-guided CFE ablation post-PVI improved procedural

success.17 In another, 2 hours of conventional CFE-mapping and ablation provided no additional

clinical benefit.5 Such discrepancies might relate to heterogeneity of CFE-mapping techniques.

Also, CFE mechanisms are incompletely understood: they may reflect slow conduction,

localized reentry, wavelet collision,18 wavebreak near high-frequency drivers,19 or locations of

y redudududucecececed d d d atatatat rrrrememememototototeeee ssss

PVI and linear ablation Furthermore right atrial CFE area was reduced after ab

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12

epicardial ganglionated plexi.20 Some of these mechanisms suggest fibrillation-maintaining

source activity, while others suggest passive/bystander activation: a crucial distinction when

judging their relevance as targets for catheter ablation.

It has been shown that PVI reduces fractionation at non-PV left atrial sites.9,10 More

recently Matsuo et al showed that, in patients with mostly lone-AF, linear lesions additionally

reduced CFE at remote left atrial sites.21 These studies examined patients without significant

structural heart disease and minimal atrial dilatation (mean 40-45mm). In contrast, our study

examined a model of more advanced atrial disease (LA dilatation and LV dysfunction) and,

uniquely, the impact of left atrial ablation on RA-CFE, finding a significant reduction of remote

CFE-area and implying bystander activation which may partly explain the lack of benefit from

routine right atrial CFE ablation.22 If CFE represent sites of AF-maintaining (not bystander)

activity, reduction of remote CFEs by ablation in a lone-AF model could suggest acute

electrophysiological remodelling. Our data, in a conceivably less reversible atrial substrate

associated with chronic stretch and fibrosis,11,12 demonstrate that biatrial CFE are also reduced

by remote ablation.

Baseline CFE coverage was lower than the prior similar study amongst patients with a

less advanced atrial substrate.21 This may be related to the CFE-mapping methods utilised,

although could reflect a substrate with more disparate islands of CFE, as similarly reported by

Jadidi et al in patients with persistent AF and dilated atria,23 compared with the confluent CFE

reported in lone-AF in smaller atria.10,21 However, the relative reduction of remote-CFE post-

ablation was similar to earlier studies.10,21

Linear lesions

Although placement of complete linear lesions can be challenging, and incompleteness

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13

proarrhythmic, they improve long-term freedom from atrial arrhythmias.6,7 In addition to

preventing macroreentrant tachycardia, compartmentalisation may reduce both initiation and

maintenance of AF. Allessie et al recently performed high-density epicardial mapping of

persistent AF in humans, showing a substrate based on lines of block, rather than rotors or foci

maintaining AF, with longitudinal dissociation facilitating multiple wavefronts.24 A recent study

examined the impact of linear lesions on the atrial substrate based upon the change in spectral

components below the dominant frequency. These components were more prevalent in those

with AF persistence, and complete linear lesions – but not PVI or CFE ablation – led to their

reduction and elimination.25 Alteration of AF wavefront propagation and elimination of spectral

components may explain our observed reduction in CFE and the favourable clinical outcome

from robust linear lesions.

Sequence of ablation in a stepwise approach

The ideal ablation strategy for persistent AF remains uncertain. Stepwise ablation, including

PVI, CFE-targeting, and linear lesions, can lead to favourable outcomes.7,8 If one intends to

ablate CFE, our data support following PVI with linear lesions to minimize unnecessary CFE-

ablation,21 which itself may be proarrhythmic.26 Some CFE may facilitate ongoing AF:3 in our

study ablation of residual LA-CFE after linear ablation prolonged AF cycle length, and

terminated AF in a handful of cases.

Procedural outcome

The high single-procedure success mirrors that reported after similarly extensive ablation,8

although a smaller proportion of our patients had procedural AF-termination. AF-termination

showed a trend towards predicting improved outcome in our cohort, but termination was not

necessary for long-term success in the majority. The long procedure times inherent to our

E ablation – led to o ththththee

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ablation strategy for persistent AF remains uncertain. Stepwise ablation, includin

targeting and linear lesions can lead to fa o rable o tcomes 7,8 If one intends to

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14

mapping and ablation protocol provided a long waiting time after PVI and linear lesions, which

possibly contributed to the improved outcome.27 Prior failure of antiarrhythmic drugs or DC

cardioversion (present in only a third and half respectively) were not inclusion criteria for the

study. Hence, the AF in this population might have been less resilient than that in previous

studies.

Limitations

This study has several limitations. The detection threshold was investigator-customised and

fixed for each patient, thus atrial CFE coverage may not be comparable to prior studies, and it is

possible that some very-low-voltage CFE were missed. To minimize procedural duration we did

not acquire multiple RA-CFE maps and hence cannot comment on the component effects of

stepwise ablation on the RA-CFE-area. To minimize arrhythmia recurrence in this challenging

population, we applied all contemporary ablation strategies rather than comparing them; hence,

component impact on outcome is uncertain, however the on-going STAR-AF II study

(ClinicalTrials.gov NCT01203748) is investigating this. The small number of patients with

unblocked lines after ablation limits interpretation of impact on outcome. Whilst the study

complied with the minimal ECG-monitoring recommended by the HRS/EHRA/ECAS

2007/2012 consensus statements, silent AF episodes may have been missed in those without

implanted devices. However, sinus rhythm at multiple visits suggests significantly reduced

arrhythmia burden post-persistent AF ablation.

Conclusions

In patients with persistent AF associated with LV systolic dysfunction, high-density contact

mapping revealed that PVI and linear lesions each had a significant effect in reducing LA

fractionation at sites remote from ablation. LA ablation also led to a reduction in RA

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15

fractionation. A significant proportion of the CFE seen in the untreated atrium in this model of

advanced atrial substrate were thus abolished by ablation at remote sites, which could suggest

that at least some CFE represent incident activation rather than source activity. Completeness of

linear lesions was associated with both greater CFE reduction and improved procedural outcome.

Targeting CFE after PVI and linear lesions may minimize unnecessary collateral damage to atrial

myocardium, and this ablation strategy was associated with a low rate of atrial fibrillation

recurrence.

Acknowledgments: The study was supported by the NIHR Cardiovascular Biomedical Research

Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London.

We are most grateful to Winston Banya for his assistance with statistical analysis.

Funding Sources: Drs Jones and Haldar were supported by an educational grant from St Jude

Medical, UK.

Conflict of Interest Disclosures: None.

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S u

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f Interest Disclos res N

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S, Nault I,, Chauhhanananan VBBBBorororordadadadachchchcharararar PPPP, , , JaJaJaJaisis PPPP, ,succcesessfsfff lullul ttttrereatatmemememennntnt

MLr ad

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bstrate after circ mferential p lmonar ein isolation of atrial fibrillation Ci

MMMMDD,DD Wrighhhhtt t M,M,M,M KKnenenechchchht ttt S,S,S, JJJaiaaia s P,P,P, HHHocococinii i M,M TTTakakakakahahahahassshhihihi YYY,,, JoJoJoJ nssoooson nnn A,A,A,A SSSacacaccheheherrr r F,F LLLiL mmm m KT, Aranntees L,L,L, Derere vvval N,NNN LLLeelloucucche NN, NaNaNaN ululullt I, BBBooordaacchararar PP, ClClCllememmennty J,,, rreee MMM. Longngngg-teermm fffollowww-upupupu ooof fff ppperrsr isssteeent attriaaaalll fibbbrb iillaaatiiiion aabblatatttioooon ussssininingg ttermmminnaduralll eneneendpdpdpdpointttt. EEEuE r HHHeH art tt JJJJ. 22202 09999;3;3;3;30:0:0:0 1111111 0505050 1-11111111222.2 JJJJ

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CA, Novak P,, CallzozozozolalAAAAblblblblatatatatioioioion nnn fofofoforr rr ReReReRedududuductctctc ioioooal triaiallll. EEEuEur r HHeHeH arartttt JJJJ.JJ

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JKm ihe isolated sheep heart d ring atrial fibrillation Ci l ti 2006;113:626 633

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24. Allessie MA, de Groot NM, Houben RP, Schotten U, Boersma E, Smeets JL, Crijns HJ. Electropathological substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: longitudinal dissociation. Circ Arrhythm Electrophysiol. 2010;3:606-615.

25. Yokokawa M, Chugh A, Ulfarsson M, Takaki H, Han L, Yoshida K, Sugimachi M, Morady F, Oral H. Effect of linear ablation on spectral components of atrial fibrillation. Heart Rhythm.2010;7:1732-1737.

26. Chen M, Yang B, Chen H, Ju W, Zhang F, Tse H-F, Cao K. Randomized Comparison Between Pulmonary Vein Antral Isolation versus Complex Fractionated Electrogram Ablation for Paroxysmal Atrial Fibrillation. Journal of Cardiovascular Electrophysiology. 2011;22:973-981.

27. Cheema A, Dong J, Dalal D, Marine JE, Henrikson CA, Spragg D, Cheng A, Nazarian S, Bilchick K, Sinha S, Scherr D, Almasry I, Halperin H, Berger R, Calkins H. Incidence and time course of early recovery of pulmonary vein conduction after catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2007;18:387-391.

Table 1. Baseline characteristics(n=30)

Mean±SD Median IQRAge(years) 63±10 62 56-71Gender(male/female) 25/5History of AF(months) 50±38 44 20.5-72Current AF episode(months) 24±21 16.5 6.25-36History of heart failure(months) 63±58 54 21-75LA diameter(mm) 50±7 49 46-51.75LV ejection fraction(radionuclide,%) 24±9 26.5 16.5-30BNP(pg/ml) 406±334 286 183-566BMI(kg/m2) 29±5 29 25-32Coronary artery disease 12(40%)Diabetes mellitus 7(23%)Beta-blockers 28(93%)Angiotensin/aldosterone-blockade 30(100%)Amiodarone 3(10%)Implanted device(of which CRT) 10(8)

pphyysiologgyy. 2011;2;2222:2:22 9

Chenennngggg AAAA NNNNazazazazarararariaiaiaiannK, Sinha S, Scherr D, Almasry I, Halperin H, Berger R, Calkins H. Incidence andearly recovery of pulmonary vein conduction after catheter ablation of atrial fibria

K, SiSiSinhnhnhhaaa S,S,S,S SSSchhhererere r D, Almasry I, Halperinnnn HHH, Berger R, CaCC lkkkkininins H. Incidence andeaaaarrlrr yyyy recoveeeeryryry oooof pupupup lmlmlmonooo ararrary y y vevvv ininin cononondudd cttioion afaffafteteteter r r r cacaththththetetete ererer aaaablbb attioooion nnn ofofof aaatrrrtriaiaiai lll fifififibrb iassscs EElectrophyysiiol. 22200777;18:383838387---3391..

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Table 2. Cox-regression analysis model for atrial arrhythmia-free survival after a single ablation procedure(n=30)

univariable multivariable

Variable HR 95%CI p HR 95%CI p

Age/year 0.99 0.93-1.06 0.77Female gender 0.60 0.16-2.31 0.46LA size/5mm 1.80 1.09-2.97 0.022 1.66 0.93-2.98 0.09Implanted device 2.02 0.60-6.84 0.26

Ischaemic HF 2.02 0.61-6.69 0.25

LV ejection fraction/5% 0.90 0.63-1.29 0.56

AF duration/months 1.01 0.98-1.04 0.41Baseline LA-CFE-area/cm2 1.01 0.96-1.07 0.62Baseline RA-CFE-area/cm2 1.00 0.96-1.05 0.85Change in LAA CL/5ms 1.13 0.91-1.40 0.28Change in LA-CFE-area/cm2 0.92 0.09-9.80 0.95AF-termination 0.03 0.00-11.44 0.25Total RF-duration/per 10min 0.98 0.70-1.37 0.91CFE RF-duration/5min 1.09 0.71-1.66 0.69Unblocked LL 7.49 1.74-32.16 0.007 4.69 1.05-21.06 0.04

HR=Hazard Ratio, CI=confidence interval, p=p-valueAF=atrial fibrillation, CFE=complex fractionated electrogram, CL=cycle-length, HF=heart failure, LA=left atrial, LL=linear lesion, LV=left ventricular, RA=right atrial, RF=radiofrequency ablation

Figure Legends:

Figure 1. Summary of ablation and CFE-mapping protocol

RA=right atrium, LA=left atrium, PVI=pulmonary vein isolation,

CFE=complex fractionated electrograms, LL=linear lesions, CTI=cavotricuspid isthmus

Figure 2. Sequential left atrial CFE maps. High-density LA-CFE-mean maps at baseline and

after stepwise ablation. Example electrograms are arrowed: yellow marks show electrograms

AAira

LR ti CI fid i t l l

AAAA A CCCLC /555msmms 1.13 0.91-1.40 0.28AAAA-CCCFC E-area/c/c/cmmm2 00.00 92929292 0.0.00 0999-9.80 0.95555iooonnn 0.03033 0...0000000 -1111.444444 0.25555ration/nnn per / 1010101 minnn 0.9888 0.70-1.337 7 0.00 91atioooon/n/n//5m5m5m5 ininin 11.1 09090909 0.71717171-1-1-11.666666 6 0.000 69696969

LL 7..49494949 1.1.1.7474747 -3-3-32.2.2.2 16161616 0.0.0.0 000000 777 4.4.4.4 696969 1.1.1.1 0505050 -2-2-21.1.1..0606060 0.00 04RR iti CCII ffidid ii t ll ll


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contributing to the CFE-mean.

Figure 3. Sequential right atrial CFE maps. High-density RA-CFE maps at baseline and after all

LA ablation. Electrograms are shown from the lateral wall pre/post ablation, displaying marked

organisation of a prior CFE site.

Figure 4. Biatrial geometry and segmentation. A. Left atrium: anterior, posterior and appendage.

MVI=mitral valve isthmus. B. Right atrium: lateral, septal, and appendage. TVA=tricuspid

valve annulus

Figure 5. Impact of stepwise ablation on CFE-area. The percentage(mean±SD) of atrial

surface(excluding PVI and linear lesion sites) covered by CFE is shown, segmented as per figure

4. P-values denoted*<0.05,**<0.01,***<0.001. A. Left atrium: baseline, post-PVI, post-linear

lesions (LL), and post-CFE ablation. B. Right atrium: baseline and after all LA ablation

dagge. TVA=tricusussspipipip d

I

c

s n

L) and post CFE ablation B Right atri m: baseline and after all LA ablation

Immmmpppap ct of stepwiw se aabbblattttioioioon onon CFCFFE-araarea. TThe pepepepercrcrcrceentttaggge(mmeean±n±n±SD)))) oofo aattrialll

cludddininininggg PVPVPVPVI anddd liliilinear lesioioioion sites)s)s)s) cooovereddd d bybyby CCCCFEFEFEFE is shshshshown, segmgmgmgmenteddd as per

s denoted*d*d*<000.00005,******* 0<00 00.01,11 ******* *<000.0000001111. A. LLeL ftftff atrt iuii m: babababaselililinenenee, popp stt-PVPVPVII,II popopopostststst-lin

L)L) dd tst CFCFEE babllatiti BB RiRi hghtt tat iri bba lili dd faftte lalll LALA blbl tatiio


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and Tom WongDavid G. Jones, Shouvik K. Haldar, Julian W.E. Jarman, Sofian Johar, Wajid Hussain, Vias Markides

Fibrillation and Heart FailureImpact of Stepwise Ablation on the Bi-Atrial Substrate in Patients with Persistent Atrial

Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2013 American Heart Association, Inc. All rights reserved.

Dallas, TX 75231is published by the American Heart Association, 7272 Greenville Avenue,Circulation: Arrhythmia and Electrophysiology

published online July 23, 2013;Circ Arrhythm Electrophysiol.

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