Substrate Ablation Without Pulmonary Vein Isolation

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 69, NO. 3, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2016.11.022

EDITORIAL COMMENT

Substrate Ablation Without Pulmonary Vein Isolation A Reasonable Proposition for Atrial Fibrillation Ablation?* John Hummel, MD

C

urative ablation of atrial fibrillation (AF) has

of a seemingly ill-fated approach designed to ablate

evolved significantly since pulmonary vein

AF without PVI. The authors employed a novel map-

isolation (PVI) was initially verified as an

ping technique using a 20-pole PentaRay catheter

ablative approach to eliminate AF. However, the fact

(Biosense Webster, Diamond Bar, California) to iden-

that successful PVI rarely converted patients to sinus

tify regions of spatiotemporal dispersion of electrical

rhythm (SR), and was less successful in maintaining

activation as an important AF substrate and targeted

SR in more persistent forms of AF, fueled the search

these sites for ablation. Dispersion areas were defined

for targetable substrates responsible for sustaining

as electrogram clusters, either fractionated or non-

AF. Use of stepwise linear ablation or complex frac-

fractionated, that displayed interelectrode time and

tionated atrial electrogram (CFAE) ablation alone or

space dispersion at a minimum of 3 adjacent bipoles

together with PVI yielded no significant benefit over

such that activation spread over the entire AF cycle

straightforward PVI (1). Other approaches, such as

length. The endpoint of ablation of dispersion areas

focal impulse and rotor modulation (FIRM) ablation,

was AF termination defined as conversion to SR or a

box isolation of fibrotic areas, and ablation of low-

stable atrial tachycardia (AT), which was mapped and

voltage areas with certain electrical signatures, hold

ablated until conversion to SR. The procedure was

promise but only appear useful as adjuncts to PVI

performed at 3 centers in 105 patients with parox-

(2–4). Furthermore, data from surgical studies sug-

ysmal, persistent, or longstanding persistent AF

gest that, in some patients, atrial remodeling with

refractory to antiarrhythmic medication and naive to

associated longitudinal and endoepicardial dissocia-

prior ablation. Their outcome was compared to a

tion and accompanying multiple wavelets with wave

retrospectively collected validation set of AF patients

break and re-entry may involve the entire atrial wall

following standard PVI or a stepwise approach

as the sustaining substrate, clouding hope for target-

matched for sex, presence of structural heart disease,

able drivers (5). Thus, PVI remains the cornerstone of

and duration of continuous AF.

AF ablation as the one intervention that seems to achieve some success in maintaining SR. SEE PAGE 303

The study’s main findings were that ablation of dispersion areas without PVI produced termination of AF to SR in 15% or AT in 80% of patients (95% AF termination). Subsequent mapping and ablation of

Despite multiple studies attesting to the impor-

approximately 1.9 ATs per patient resulted in an

tance of PVI in AF ablation, in this issue of the

overall ablation to SR in 77% versus approximately 20%

Journal, Seitz et al. (6) present the positive outcome

for the validation set. Dispersion mapping and ablation produced a procedure time and radiofrequency time that were approximately 60 min and 36 min shorter,

*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Ohio State University Wexner Medical Center, Columbus, Ohio.

respectively, than the validation set. With nearly 44% of patients on antiarrhythmic medication in both groups, the single-procedure AF recurrence rate at 18

Dr. Hummel is a consultant for Abbott Electrophysiology and Biosense

months was 11% for the study group versus 58% for the

Webster.

validation set; for AF/AT, it was 45% versus 65%.

Hummel

JACC VOL. 69, NO. 3, 2017 JANUARY 24, 2017:322–4

Atrial Fibrillation Ablation without Pulmonary Vein Isolation: Reasonable?

Although patients with longstanding persistent AF

because other studies have found the PVs to be the site

required more ablation, there was no difference in

of highest DF and source of the LA-right atrial DF

long-term outcome between paroxysmal, persistent,

gradient (8). Furthermore, the lack of spatial stability

and longstanding persistent AF patients in the study

of DF in LA sites in other series raises a question as to

group. There also appeared to be no difference in long-

whether sites of high DF can serve as a surrogate for

term outcome based upon whether mapped AF was

these dispersion sites that appear to have spatial sta-

spontaneous or induced.

bility (9). The study also had clinical limitations in that

In terms of the mechanistic assessment, numerical

the true success rate is likely overestimated because

computer simulations of drivers (represented as ro-

44% of patients remained on antiarrhythmic medica-

tors or micro–re-entry) in fibrotic substrate confirmed

tion and post-ablation monitoring was mostly limited

dispersion patterns at the driver core without

to 4 days over 1.5 years via Holter monitor. Only 20

dispersion at this activity’s periphery. Optical map-

patients had a 7-day monitor, and 2 had implantable

ping experiments on ovine left atrial (LA) scar models

device recordings. Additionally, although helpful, use

demonstrated similar findings. The assessment sug-

of a validation set is no substitute for a prospective,

gested that dispersion electrograms represent rotors

randomized trial. In fact, earlier findings from the

or micro–re-entrant drivers where the wave front is

long-term outcome of patients who underwent a

highly curved and impulse propagation of waves

stepwise ablation procedure for persistent AF showed

emanating from drivers is impaired by fibrotic sub-

AF was terminated during ablation to SR in 25% and to

strate. They also showed that CFAEs located in non-

AT in 75% (10). Among the latter, further ablation

dispersion regions represented most of the CFAE

yielded SR in 83%. Arrhythmia-free outcomes were

surface area and that approximately 30% of the

z90%, 80%, and 63% at 1, 2, and 5 years, respectively,

surface area in dispersion regions was CFAE-free,

off antiarrhythmic medication (10). Thus, a prospec-

consistent with the inability to demonstrate clear

tive randomized study would provide greater assur-

benefit from CFAE ablation.

ance of a superior approach. Also, although the

The single observation of a successful AF ablation

operators in the current study appeared to have

approach without PVI is a startling claim, demanding

reproducible interpretation of the dispersion sites, the

close examination. It appears that the preponder-

order of targeting was based on a subjective selection

ance of recurrence in the study group was AT and

of sites that were seemingly activated the fastest. This

mostly AF in the validation set, supporting the

is worrisome for potential reproducibility of these

contention that the targeted dispersion sites in the

findings. When the results are considered from the

study group are critical for AF maintenance. It could

rigorous endpoint of the percentage of patients

be that the remaining ATs in the study group were

without any atrial arrhythmia and off antiarrhythmic

from typical sites of AF triggers such as the pulmo-

medication, the recurrence rate of 45% with 44% on

nary veins (PVs), but probably not, given that one-

antiarrhythmic medication raises the question as to

half

how this technique will hold up against such an

were

macro–re-entrant.

Unfortunately,

the

remaining ATs were only categorized according to

exacting standard.

proximity to dispersion areas and not anatomic

However, these issues should not distract from

location. The unusual preponderance of macro–re-

the real point: these data provided us with both

entrant AT after dispersion ablation also raises the

mechanistic and clinical insights that question PVI’s

question of proarrhythmia from the dispersion lesion

fundamental importance. Mechanistically, the re-

set. The authors pointed out that the approach was

sults appeared to reaffirm the existence of AF

equally effective for all types of AF, but 44% of

drivers outside the PVs that can be targeted using

patients were still on antiarrhythmic medications in

spatiotemporal dispersion and are associated with

unclear percentages per type of AF, which may

regions of fibrosis that may help to target these

account for the lack of outcome disparity between

areas. Clinically, these findings suggested that the

different AF types.

foundational importance of PVI in AF ablation is

Their observation that multipolar electrogram

open to question. Even if lack of PVI means that we

dispersion also depended on the source’s frequency of

will chase ATs with redo procedures, they imply we

activation supported studies that have targeted areas

may be able to attain AF/AT-free survival rates of

of high dominant frequency (DF) as AF sources or have

83%, 84%, and 87% in paroxysmal, persistent, and

shown such sources as important predictors of

longstanding persistent AF without PVI. The overall

outcome after PVI (7). If their suggestion holds true,

point of this study’s findings: areas outside the PVs

that areas of highest DF are a marker for dispersion

critical to AF maintenance exist and their elimina-

regions, then the absence of PVs as a target is troubling,

tion may make the presence or absence of triggers

323

324

Hummel

JACC VOL. 69, NO. 3, 2017 JANUARY 24, 2017:322–4

Atrial Fibrillation Ablation without Pulmonary Vein Isolation: Reasonable?

from the PVs less relevant in reestablishing and

the success and reproducibility of approaches that are

maintaining SR.

additive to PVI, let alone absent PVI itself. Further-

The authors’ reference to studies of substrate abla-

more, the notion that repetitive PV tachycardia can

tion by Narayan et al. (2) and Jadidi et al. (4) could also

promote remodeling remains unaddressed by an AF

include other studies that demonstrated the potential

ablation strategy that omits PVI.

importance of targeting non-PV substrate, but have yet

This study is undoubtedly provocative because it

to demonstrate the effectiveness of this approach

challenges the premise that PVI is the “cornerstone”

without PVI (2–4). This study showed that interstitial

of AF ablation, holding forth the promise of a poten-

fibrosis is essential to the observation of spatiotem-

tially effective or more effective ablation approach

poral dispersion of electrograms during AF, lending

with shorter procedural and fluoroscopy times and a

credence to the findings that fibrotic substrate in hu-

reduction in radiofrequency energy. The notion that

man hearts can support micro–re-entrant drivers,

we can tailor the ablation to a particular patient’s

predict outcomes of AF ablation, and serve as ablation

disease is an idea that will not go away, because the

targets (11,12). The essential presence of fibrosis in

approach of PVI alone for all ignores the significant

supporting drivers might also help improve ablation

variability in underlying substrate between patients.

outcomes using other techniques, such as FIRM abla-

We look forward to the investigations to come.

tion, by tying targeted FIRM-detected rotor sites to regions of scar on pre-operative atria imaging.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

Despite this study’s observations, it is difficult to

John Hummel, The Ohio State University Wexner

believe that targeting these dispersion regions may

Medical Center, 473 West 12th Avenue, Suite 200,

allow a PVI-free ablation and yield a better result. To

Columbus,

date, no randomized trial adequately reassured us of

osumc.edu.

Ohio

43210.

E-mail:

john.hummel@

REFERENCES 1. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–22. 2. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel W-J, Miller JM. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012;60:628–36. 3. Kottkamp H, Berg J, Bender R, Rieger A, Schreiber D. Box isolation of fibrotic areas (BIFA): a patient-tailored substrate modification approach for ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2016;27:22–30. 4. Jadidi AS, Lehrmann H, Keyl C, et al. Ablation of persistent atrial fibrillation targeting low-voltage areas with selective activation characteristics. Circ Arrhythm Electrophysiol 2016;9:e002962. 5. De Groot N, Van der Does L, Yaksh A, et al. Direct proof of endo-epicardial asynchrony of the atrial wall during atrial fibrillation in

humans. Circ Arrhythm Electrophysiol 2016;9: e003648. 6. Seitz J, Bars C, Théodore G, et al. AF ablation guided by spatiotemporal electrogram dispersion without pulmonary vein isolation: a wholly patient-tailored approach. J Am Coll Cardiol 2017;69:303–21. 7. Yokoyama E, Osaka T, Takemoto Y, et al. Paroxysmal atrial fibrillation maintained by nonpulmonary vein sources can be predicted by dominant frequency analysis of atriopulmonary electrograms. J Cardiovasc Electrophysiol 2009;

fractionated atrial electrograms activity and dominant frequency in human atrial fibrillation. J Arrhythm 2015;31:101–7. 10. Scherr D, Khairy P, Miyazaki S, et al. Five-year outcome of catheter ablation of persistent atrial fibrillation using termination of atrial fibrillation as a procedural endpoint. Circ Arrhythm Electrophysiol 2015;8:18–24. 11. Hansen B, Zhao J, Csepe T, et al. Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explan-

20:630–6.

ted human hearts. Eur Heart J 2015;10:1–12.

8. Okumura Y, Watanabe I, Kofune M, et al.

12. Akoum N, Daccarett M, McGann C, et al. Atrial

Characteristics and distribution of complex fractionated atrial electrograms and the dominant frequency during atrial fibrillation: relationship to the response and outcome of circumferential pulmonary vein isolation. J Interv Card Electrophysiol 2012;34:267–75.

fibrosis helps select the appropriate patient and strategy in catheter ablation of atrial fibrillation: a DE-MRI guided approach. J Cardiovasc Electrophysiol 2011;22:16–22.

9. Kogawa R, Okumura Y, Watanabe I, et al. Spatial and temporal variability of the complex

KEY WORDS ablation, atrial fibrillation, dispersion, driver