New mechanism-based approaches to ablating persistent AF - will drug therapy soon be obsolete?

Journal of Cardiovascular Pharmacology Publish Ahead of PrintDOI: 10.1097/FJC.0000000000000270

New mechanism-based approaches to ablating persistent AF –

will drug therapy soon be obsolete?

Junaid A.B. Zaman MA, MD, Tina Baykaner MD, MPH and Sanjiv M. Narayan, MD,

PhD

Department of Cardiovascular Medicine, Stanford Medicine, Stanford, CA 94305.

Keywords: Atrial fibrillation, ablation, rotors, focal sources, drugs

Disclosures:

This work was supported by grants to Dr. Narayan from the NIH (HL70529, HL83359,

HL103800) and the Doris Duke Charitable Foundation. Dr. Narayan is co-author of

intellectual property owned by the University of California Regents and licensed to

Topera Inc. Dr. Narayan is a consultant to Abbott Inc., Medtronic, and the American

College of Cardiology. Dr Zaman has no conflicts of interest to declare.

Corresponding Author:

Sanjiv Narayan

Stanford Medicine

780 Welch Road, Suite CJ250F, Stanford, CA 94305

[email protected]

ACCEPTED

Copyright © 201 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.5

2

Word Count: 2883

Abstract (171 words)

Persistent atrial fibrillation (AF) represents a major public health and medical

challenge. The progressive nature of the disease, high morbidity and increasing

health-economic costs ensure it remains at the forefront of novel research into

mechanisms and potential therapies. These are largely divided into pharmacological

(drugs) and electrical (ablation), with patients often going from former to latter. AF

ablation has improved sufficiently to be offered as first line for paroxysmal AF, but

there is uncertainty on whether drug therapy will improve from its current role or be

relegated to niche status. In this review we shall outline the progress in mechanistic

understanding of AF that may allow results from ablation to diverge dramatically

from drug therapy, to identify populations in whom drug therapy may become less

relevant. We end by looking ahead to future developments which we hope will spur

on therapeutic efficacy in both fields.

ACCEPTED


3

1. Introduction

The treatment of atrial fibrillation (AF) has been revolutionized in the last decade.

While many trials show that maintaining sinus rhythm using anti-arrhythmic drugs

(AAD) is equivalent to a rate control strategy, shown in the AFFIRM 1, RACE-I 2 and

AF-in-CHF 3 trials, these results are specific to AAD therapy. Notably, current AAD are

limited by a relatively poor rate of maintaining sinus rhythm 4 and side-effects

including elevated cardiovascular mortality 5.

Ablation is a non-pharmacological alternative to AAD that has changed the

landscape for managing AF. Multicenter trials show that ablation is more effective

than AAD in eliminating AF in patients with AF despite at least one AAD 6–8 and in

patients who have never used class I or III AAD 9,10. Ablation may also be more cost

effective than AAD 11–13. Moreover, the approach to ablation has advanced rapidly

in recent years catalyzed by human mechanistic studies 14 15 providing compelling

evidence that AF is maintained in many patients by localized sources that may be

amenable to direct targeting by ablation.

This enables us to turn to the provocative question posed: whether AAD are

obsolete in persistent AF – or shortly will be. Of course, this question does not have

a binary answer. It must be considered in terms of specific AF populations, the fact

that mechanistic insights into AF will likely lead to novel AAD as well as

advancements in ablation, and the fact that individuals within the ‘same‘ population

ACCEPTED


4

may have a comorbidity profile or preference favoring one therapy over the other.

This review considers these issues, grounded in the current state-of-the-art but with

a forward-looking vision based on recent trends.

2. Ablation of persistent AF – Current Strategies

Ablation is currently centered on electrical isolation of pulmonary veins (PVI) to

eliminate ectopy that can trigger AF. In patients with paroxysmal AF, PVI may be

offered in lieu of AAD 9,10 , although this is not yet recommended for persistent AF.

Nevertheless, PVI is currently most effective when combined with AAD. In a

systematic meta-analyses of published experience, the efficacy of ablation for

paroxysmal AF was 71% but 77% in patients also using AADs 16. In a recent European

registry of 1,281 patients, 12 month freedom from atrial arrhythmias in patients with

paroxysmal AF was 43.7% for ablation alone but 68.5% in patients also using AAD 17.

Many groups use AAD early after ablation, when most recurrences occur 18, to

facilitate early atrial reverse remodeling and increase longer term success. More

than one ablation procedure is often required in patients with paroxysmal AF, and in

a systematic meta-analysis the single procedure success was 54% rising to 79% after

multiple procedures at 5 years 19. Registry data also suggests that safety is worse

than reported in clinical trials17.

Currently, ablation outcomes are lower for patients with persistent AF, which is

defined as continuous AF for 1 week to 1 year rather than intermittent paroxysms,

ACCEPTED


5

and may depend less upon triggers and more upon mechanisms that sustain AF.

These mechanisms are debated. Accordingly, many empirical ablation targets have

been proposed including complex fractionated atrial electrograms (CFAEs),

suggested to represent pivot points for reentry 20, and empirical ablation lines to

interrupt macro-reentrant circuits or constrain meandering wavelets. These

approaches yield inconsistent results 21–23, which may reflect mechanistic

uncertainty in CFAE, that represent many etiologies including noise 24, as well as

lines, since macro-reentry is uncommon during AF and typical line sets may not be

sufficient to compartmentalize multiwavelet reentry. Recent trials further question

the value of ablating these targets 25 26.

In summary, current approaches to the ablation of persistent AF are suboptimal, and

actually improved when combined with AAD. Moreover, newer atrial specific AAD

may be more effective and limit pro-arrhythmic side-effects in the ventricles, as

reviewed elsewhere in the Journal. However, recent mechanistic insights from

translational studies of human AF hold the promise of improving the success of

ablation.

3. Mechanisms of human AF persistence. Can we achieve patient specific therapy?

Ideally, ablation or drug therapy should be tailored to mechanisms in each

individual. The rationale for pulmonary vein (PV) isolation is to prevent triggers in

the PVs from initiating AF by electrically isolating the PVs (figure 1). This fits with the

ACCEPTED


6

PV ectopy model of AF 27, and is supported by the efficacy of PVI in many patients

6,19,28. However, this model does not explain many observations, such as termination

of AF when a vein is only partially isolated 29, increasingly appreciated triggers

outside the PVs, AF recurrence in patients with isolated PVs 30 and the surprising

success of AF ablation in patients in whom PVs have reconnected 31,32 or were never

isolated 33–35. Thus, when the PVI procedure is successful, it may operate by

mechanisms in addition to isolation of PV-related triggers, that are difficult to

identify a priori in any given patient.

The first major mechanistic question whose clarification may improve ablation is

“how do transient triggers actually initiate AF?”. Using wide-area mapping, Schricker

et al. recently showed that the first cycles of AF after a spontaneous or induced

trigger create functional wavefront block, facilitated by dynamic conduction slowing

36 and abnormal APD dynamics 37 to initiate a single organized spiral wave or focal

driver from which activity disorganizes 38 (figure 2). Triggers thus initiate AF via a

transitional mechanism. Notably, transitional mechanisms may lie in conserved

regions in each patient – even for AF episodes triggered in diverse regions of the

atria – and are separated 2.1±1.7cm from triggers. Further studies should identify if

ablation of transitional mechanisms (i.e. sites of initiating spiral waves) may improve

outcomes and, for instance, may contribute to the success of wide-area PV isolation

that is typically 1-2 cm from PV ostia. Transitional mechanisms also suggest a role

for drug therapy that reverses conduction slowing by modulating connexins 39 or

modulating the effects of fibrosis 40.

ACCEPTED


7

The second major mechanistic question whose clarification may improve ablation is

“what maintains human AF after it is initiated?” Novel mapping techniques provide

fresh insights into this century old debate 41 between, on one hand, the non-

hierarchical concept that AF is caused by self-sustaining disorganization and, on the

other, the hierarchical model in which disorganization is driven by localized AF

sources (rotors or focal drivers). It is notable that debate is increasingly hinged on

mapping approach, since studies that recorded AF in a small field-of-view at high

density typically support the non-hierarchical model, while newer studies recording

AF in a wider field of view at lower density largely support the hierarchical model. Of

course, multiple mechanisms may co-exist in the same experimental system49.

Most studies agree that AF is characterized by re-entry in one form or another 42. In

theory, multiple small wavelets in a non-hierarchical arrangement could provide

enough heterogeneity of activation and repolarization to reach an energetically

stable equilibrium which perpetuates indefinitely 43,44. Each wavelet has a finite

probability of encountering a nonconducting obstacle and terminating yet, if the

number of concurrent wavelets is sufficiently large, this probability is low enough to

produce persistent or ‘permanent’ AF 45. Small wavelets with no apparent order

may rapidly form and extinguish in computer models 46 and have been supported by

high density electrode mapping of small fields-of-view in humans and animals 47,48.

Conversely, the non-hierarchical model has been challenged by a ‘hierarchical’

model supported by stereotypical observed activation patterns 50, electrogram

morphologies 51, and stable frequency gradients between left and right atrium 52 in

ACCEPTED


8

AF. Other studies show that persistent AF can be eliminated by focal treatment 29,

supporting a model in which that localized sources drive downstream disorganized

wavelets. AF sources meet criteria for a ‘rotor’ if they are reentrant, or are

otherwise classified as ‘focal’ with the downstream disorganization in each case

termed ‘fibrillatory conduction’ 53.

This hierarchical paradigm was recently validated in human AF with the

demonstration of stable rotors in a large proportion of AF patients typically referred

for ablation. Ablation of these sources was able to eliminate AF acutely and on long-

term follow-up with greater success than PVI alone 14. This finding reconciles many

disparate observations which are difficult to explain by the non-hierarchical model,

such as how focal ablation could ever terminate persistent AF. Recent work from a

different non-invasive approach confirms the presence of high frequency rotors with

phase mapping in a 70/30% left/right atrial split, similar to findings from endocardial

contact baskets15. Despite technical differences between approaches, their results

agree that limited patient-specific atrial areas harbor sources that maintain AF and

are limited to these same atrial areas for days. It is beyond the scope of this review

to fully speculate on technical differences between approaches, that will only be

resolved by directly comparing techniques, but many groups have shown re-entrant

circuits in human AF54,55 and many reports show that AF can be treated by limited

interventions that do not limit critical mass. Further work is needed to extend these

physiological insights. A recent 5 year white paper on research strategy for the Heart

Rhythm Society lists mechanistic clarification of human AF among its highest

priorities 56.

ACCEPTED


9

4. Using mechanisms to guide ablation: Will Drug Therapy Soon Be Obsolete?

Single center and multicenter non-randomized trials show that ablating localized

sources can improve ablation outcomes for persistent AF. Initial clinical data were

produced using contact mapping (Focal Impulse and Rotor Modulation, FIRM) in

patients predominantly with persistent AF who had already failed at least one AAD

agent. In the CONFIRM trial, FIRM-guided ablation improved the single procedure

elimination of AF to 82.4% from 44.9% for PVI-based ablation alone on medium term

14 and then 3 year follow up (figure 3A) 57. These results have been supported by

multicenter trials mechanistically 58,59 and clinically 60. Other groups have shown

sources using various methods (figure 3B) 15,54,55.

There are several unanswered questions on the source model for AF that may

impact ablation. First, there is a need for randomized trials to confirm these

promising multicenter data. Second, it is not established how best to ablate sources.

Third, it is unclear whether the endpoint of ablation should be AF termination – and

indeed it is mechanistically unclear why acute AF termination often does not predict

long-term AF elimination in conventional ablation trials. Other questions include

whether AAD have a role in preconditioning the atria 61 or facilitating reverse

remodeling after ablation, and the interplay between targeted source ablation and

PVI.

5. Mechanisms that Modify AF Substrates and May Influence Ablation

ACCEPTED


10

The cardiac autonomic nervous system (CANS) is a rich network of localized ganglia,

afferent and efferent parasympathetic and sympathetic nerve fibers, that can

promote AF by globally or regionally shortening the effective refractory period 62 and

possibly slowing conduction by the mechanism of accentuated antagonism 63.

Ablation of tissue encompassing cardiac ganglionated plexi, at stereotypical locations

often near junctions between the atria and major thoracic veins, has been shown to

improve ablation outcome 64. Studies are underway to address whether targeting

ganglia is the optimal approach to modulate the CANS, how best to localize ganglia a

priori, since current methods are suboptimal, and whether the CANS lie near sites of

rotors or focal sources or contribute to multiwavelet reentry.

An increasingly discussed mechanism is how structural remodeling of the atrium

contributes to AF. Recent MRI studies have revealed structural abnormalities outside

the PVs in AF patients that predict poor response to PVI 65. In theory, ablation of the

scar border zone with viable atrium may eliminate arrhythmogenic mechanisms.

Such areas are difficult to define in thin-walled atria given the 1-2 mm resolution of

MRI, and may or may not 66,67 represent fibrosis. Nevertheless, empirical ablation of

such regions may improve outcomes. Since this goal may reach beyond the spatial

resolution of atrial MRI reconstruction and the ablation electrode itself, this is

another area in which novel image processing and electrogram signal processing

approaches may allow genuine signal to emerge from noise to improve ablation

targeting. On the hand, the precise localization of scar borderzone may be less

needed for drug discovery, where new AAD agents could globally homogenize

ACCEPTED


11

heterogeneities that promote re-entry 68 by modulating specific membrane-sensitive

ion channels, fibrosis or cell-to-cell gap junction coupling.

6. Different populations, same disease. Can we treat all AF the same?

There will certainly be populations in whom mechanistically targeted ablation will be

most effective, in whom drug therapy is most likely to become second line (and

possibly “obsolete”). The field is evolving rapidly, but such populations likely include

ablation of AF in patients with early persistent AF (perhaps under 6 months of

continuous AF) or with paroxysmal AF. The numbers of patients treated with

mechanistically-targeted ablation with longstanding persistent AF (i.e. AF for one or

more years continuously) thus far is relatively small, and may include patients in

whom AF may represent a late-stage process from diverse comorbidities and in

whom additional data are needed.

There is increasing evidence that age is no bar to offering ablation, despite a recent

European recommendation to offer it first to youngest patients 69. Being older does

not necessarily cause atrial fibrosis per se, since recent studies show that the

historical duration of AF is more strongly associated with adverse remodeling than

age 70. This is also supported by recent data showing respectable ablation outcomes

in patients over 75 years of age 71 that reinforce earlier meta-analyses and registry

data 72,73. However, many trials excluded patients above 75 years of age and some

studies report that ablation outcomes are inferior in this population 74. Early data

from mechanistically-targeted ablation suggests no clear association between age,

ACCEPTED


12

number of AF sources and ablation outcome 15,75. On the other hand, the elderly

represent a population in whom medication side-effects are felt most keenly, in

particular the adverse impact of poly-pharmacy on patients with impaired renal

function, and studies should further compare individual mechanism-targeted

ablation strategies versus AADs in this population.

Obesity is increasingly felt to cause a complex metabolic milieu producing substrates

for AF 76. Accordingly, patients with higher BMI may experience poorer outcomes

from current ablation strategies, and promising new data show that aggressive risk

factor modification can improve ablation outcomes 77. In recent subgroup analyses

of the CONFIRM trial, patients with raised BMI and obstructive sleep apnea showed

a higher number of AF sources often remote from the PVs, but because these

sources were mapped the benefit of mechanistically targeted ablation was

retained78.

Finally, it is increasingly suggested that AF is but one manifestation of an atrial

cardiomyopathy, in which case classifying patients on this basis may improve

treatment 79. Long standing persistent AF is often refractory to AAD, by definition,

and is associated with more extensive structural remodeling classified as Utah Stage

IV on MRI 80. It is possible that mechanistically focused ablation may offer benefit for

these patients, since initial long term data suggest that outcomes are maintained 57

15. Conversely, such patients may represent ‘burnt-out’ AF disease, as suggested by

extremely complex activity on limited area high density surgical mapping 47.

ACCEPTED


13

7. Novel Approaches.

It is plausible that therapeutic options to target specific mechanisms beyond AAD

and ablation will enter clinical practice in the medium term. These include stem cell

therapy, genetic targeting, autonomic neural modulation and sophisticated hybrid

(combined surgical and endocardial) procedures 81. Drug development will continue

in parallel with refinement of ablation – just as novel oral anti-coagulants have

emerged at the same time as left atrial appendage occlusion devices. Thus, a new

synergy is likely to emerge, with pharmacological modulation of substrate

complemented by electrical modulation of drivers and mechanistically targeted,

limited ablation.

New mechanistic insight for well established drugs is emerging – such as in

catecholaminergic polymorphic ventricular tachycardia (CPVT) 82 in which there are

emerging roles for AADs such as the ability of flecainide to block ryanodine receptors

as well as sodium channels. In AF, new drug combinations such as amiodarone and

ranolazine may achieve better results with fewer side effects, especially in patients

with left atrial dilatation83. An inexorable trend in medicine is from invasive to less

invasive, and as mechanisms become better defined it is our hope that in AF this rule

will also be followed.

At the current time, three major questions need to be answered for mechanistically-

targeted ablation. First, multicenter randomized trials should be performed to show

its benefit over conventional strategies. Such trials are underway and initial results

show promise 84. Second, the efficacy of mechanistically guided ablation must be

ACCEPTED


14

demonstrated in randomized trials compared to AAD in drug-naïve patients. Third, it

it needs to be defined if AF may still recur late after initially successful mechanistic

AF ablation, i.e. to define the natural history of AF substrate progression in this

context. In the worst case scenario it may be a matter of ‘when’ and not ‘if’ AF

recurs, from the disappointing long term results of non-mechanistic ablation 85.

However, there is room for optimism since results from rotor ablation may be

maintained at 3 years86.

Conclusions

Improved mechanistic understanding of AF will drive innovations in both drug

development and ablation. Recent translational studies and advances in

computational mapping have revealed rotors and other localized sources for AF that

can be readily identified and treated with ablation to improve success in many

patients. While AAD have an increasingly supportive rather than a central role in

many patients, they are currently far from obsolete. This situation is unlikely to

change in the medium-term. With a 5-10 year horizon, however, mechanistic clarity

from translational and basic studies may enable the identification of novel targets. If

such targets are truly localized then specific ablation approaches may become

predominant. If such targets are more spatially distributed then novel drug agents

may enjoy resurgence.

References

ACCEPTED


15

1. Brown Z, Selke S, Zeh J, K. J.; AFFIRM A COMPARISON OF RATE CONTROL AND RHYTHM CONTROL IN PATIENTS WITH ATRIAL FIBRILLATION T. The New

England journal of medicine. 2002, 347, 1825–1833.

2. Hagens, V. E.; Ranchor, A. V; Sonderen, E. Van; Bosker, H. A.; Kamp, O.; Tijssen, J. G. P.; Kingma, J. H.; Crijns, H. J. G. M.; Gelder, I. C. Van Effect of Rate or Rhythm Control on Quality of Life in Persistent Atrial Fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. Journal of

the American College of Cardiology. 2004, 43, 241–7.

3. Roy, D.; Talajic, M.; Nattel, S.; Wyse, D. G.; Dorian, P.; Lee, K. L.; Bourassa, M. G.; Arnold, J. M. O.; Buxton, A. E.; Camm, A. J.; Connolly, S. J.; Dubuc, M.; Ducharme, A.; Guerra, P. G.; Hohnloser, S. H.; Lambert, J.; Heuzey, J.-Y. Le; O’Hara, G.; Pedersen, O. D.; Rouleau, J.-L.; Singh, B. N.; Stevenson, L. W.; Stevenson, W. G.; Thibault, B.; Waldo, A. L. Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure. The New England journal of

medicine. 2008, 358, 2667–77.

4. Singh, B. N.; Singh, S. N.; Reda, D. J.; Tang, X. C.; Lopez, B.; Harris, C. L.; Fletcher, R. D.; Sharma, S. C.; Atwood, J. E.; Jacobson, A. K.; Lewis, H. D.; Raisch, D. W.; Ezekowitz, M. D. Amiodarone versus Sotalol for Atrial Fibrillation. The New England journal of medicine. 2005, 352, 1861–1872.

5. Saksena, S.; Slee, A.; Waldo, A. L.; Freemantle, N.; Reynolds, M.; Rosenberg, Y.; Rathod, S.; Grant, S.; Thomas, E.; Wyse, D. G. Cardiovascular Outcomes in the AFFIRM Trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management). An Assessment of Individual Antiarrhythmic Drug Therapies Compared with Rate Control with Propensity Score-Matched Analyses. Journal

of the American College of Cardiology. 2011, 58, 1975–85.

6. Mont, L.; Bisbal, F.; Hernández-Madrid, A.; Pérez-Castellano, N.; Viñolas, X.; Arenal, A.; Arribas, F.; Fernández-Lozano, I.; Bodegas, A.; Cobos, A.; Matía, R.; Pérez-Villacastín, J.; Guerra, J. M.; Ávila, P.; López-Gil, M.; Castro, V.; Arana, J. I.; Brugada, J. Catheter Ablation vs. Antiarrhythmic Drug Treatment of Persistent Atrial Fibrillation: A Multicentre, Randomized, Controlled Trial (SARA Study). European heart journal. 2014, 35, 501–507.

7. Wilber, D. D. J.; Pappone, C.; Neuzil, P.; Paola, A. De; Marchlinski, F.; Natale, A.; Macle, L.; Daoud, E. G.; Calkins, H.; Augello, G.; Liu, C. Y.; Berry, S. M.; Berry, D. A.; Page, P. Comparison of Antiarrhythmic Drug Therapy and Radiofrequency Catheter Ablation in Patients with Paroxysmal Atrial Fibrillation. JAMA: the journal of …. 2010, 303, 333–340.

8. Packer, D. L.; Kowal, R. C.; Wheelan, K. R.; Irwin, J. M.; Champagne, J.; Guerra, P. G.; Dubuc, M.; Reddy, V.; Nelson, L.; Holcomb, R. G.; Lehmann, J. W.;

ACCEPTED


16

Ruskin, J. N. Cryoballoon Ablation of Pulmonary Veins for Paroxysmal Atrial Fibrillation: First Results of the North American Arctic Front (STOP AF) Pivotal Trial. Journal of the American College of Cardiology. 2013, 61, 1713–23.

9. Morillo, C. a.; Verma, A.; Connolly, S. J.; Kuck, K. H.; Nair, G. M.; Champagne, J.; Sterns, L. D.; Beresh, H.; Healey, J. S.; Natale, A. Radiofrequency Ablation vs Antiarrhythmic Drugs as First-Line Treatment of Paroxysmal Atrial Fibrillation (RAAFT-2). JAMA�: the journal of the American Medical Association. 2014, 311, 692–700.

10. Cosedis Nielsen, J.; Johannessen, A.; Raatikainen, P.; Hindricks, G.; Walfridsson, H.; Kongstad, O.; Pehrson, S.; Englund, A.; Hartikainen, J.; Mortensen, L. S.; Hansen, P. S. Radiofrequency Ablation as Initial Therapy in Paroxysmal Atrial Fibrillation. The New England journal of medicine. 2012, 367, 1587–95.

11. Chan, P. S.; Vijan, S.; Morady, F.; Oral, H. Cost-Effectiveness of Radiofrequency Catheter Ablation for Atrial Fibrillation. Journal of the American College of

Cardiology. 2006, 47, 2513–2520.

12. Khaykin, Y.; Morillo, C. a.; Skanes, A. C.; McCracken, A.; Humphries, K.; Kerr, C. R. Cost Comparison of Catheter Ablation and Medical Therapy in Atrial Fibrillation. Journal of Cardiovascular Electrophysiology. 2007, 18, 907–913.

13. Khaykin, Y.; Wang, X.; Natale, A.; Wazni, O. M.; Skanes, A. C.; Humphries, K. H.; Kerr, C. R.; Verma, A.; Morillo, C. a. Cost Comparison of Ablation versus Antiarrhythmic Drugs as First-Line Therapy for Atrial Fibrillation: An Economic Evaluation of the RAAFT Pilot Study. Journal of Cardiovascular

Electrophysiology. 2009, 20, 7–12.

14. Narayan, S. M.; Krummen, D. E.; Shivkumar, K.; Clopton, P.; Rappel, W.-J.; Miller, J. M. Treatment of Atrial Fibrillation by the Ablation of Localized Sources. Journal of the American College of Cardiology. 2012, 60, 628–636.

15. Haissaguerre, M.; Hocini, M.; Denis, A.; Shah, A. J.; Komatsu, Y.; Yamashita, S.; Daly, M.; Amraoui, S.; Zellerhoff, S.; Picat, M.-Q.; Quotb, A.; Jesel, L.; Lim, H.; Ploux, S.; Bordachar, P.; Attuel, G.; Meillet, V.; Ritter, P.; Derval, N.; Sacher, F.; Bernus, O.; Cochet, H.; Jais, P.; Dubois, R. Driver Domains in Persistent Atrial Fibrillation. Circulation. 2014, 130, 530–8.

16. Calkins, H.; Reynolds, M. R.; Spector, P.; Sondhi, M.; Xu, Y.; Martin, A.; Williams, C. J.; Sledge, I. Treatment of Atrial Fibrillation with Antiarrhythmic Drugs or Radiofrequency Ablation: Two Systematic Literature Reviews and Meta-Analyses. Circulation. Arrhythmia and electrophysiology. 2009, 2, 349–61.

17. Arbelo, E.; Brugada, J.; Hindricks, G.; Maggioni, A. P.; Tavazzi, L.; Vardas, P.; Laroche, C.; Anselme, F.; Inama, G.; Jais, P.; Kalarus, Z.; Kautzner, J.; Lewalter,

ACCEPTED


17

T.; Mairesse, G. H.; Perez-Villacastin, J.; Riahi, S.; Taborsky, M.; Theodorakis, G.; Trines, S. a The Atrial Fibrillation Ablation Pilot Study: A European Survey on Methodology and Results of Catheter Ablation for Atrial Fibrillation Conducted by the European Heart Rhythm Association. European heart

journal. 2014, 35, 1466–78.

18. Tzou, W. S.; Marchlinski, F. E.; Zado, E. S.; Lin, D.; Dixit, S.; Callans, D. J.; Cooper, J. M.; Bala, R.; Garcia, F.; Hutchinson, M. D.; Riley, M. P.; Verdino, R.; Gerstenfeld, E. P. Long-Term Outcome after Successful Catheter Ablation of Atrial Fibrillation. Circulation: Arrhythmia and Electrophysiology. 2010, 3, 237–242.

19. Ganesan, A. N.; Shipp, N. J.; Brooks, A. G.; Kuklik, P.; Lau, D. H.; Lim, H. S.; Sullivan, T.; Roberts-Thomson, K. C.; Sanders, P. Long-Term Outcomes of Catheter Ablation of Atrial Fibrillation: A Systematic Review and Meta-Analysis. Journal of the American Heart Association. 2013, 2, 1–14.

20. Nademanee, K.; McKenzie, J.; Kosar, E.; Schwab, M.; Sunsaneewitayakul, B.; Vasavakul, T.; Khunnawat, C.; Ngarmukos, T. A New Approach for Catheter Ablation of Atrial Fibrillation: Mapping of the Electrophysiologic Substrate. Journal of the American College of Cardiology. 2004, 43, 2044–2053.

21. Oral, H.; Chugh, A.; Yoshida, K.; Sarrazin, J. F.; Kuhne, M.; Crawford, T.; Chalfoun, N.; Wells, D.; Boonyapisit, W.; Veerareddy, S.; Billakanty, S.; Wong, W. S.; Good, E.; Jongnarangsin, K.; Pelosi, F.; Bogun, F.; Morady, F. A Randomized Assessment of the Incremental Role of Ablation of Complex Fractionated Atrial Electrograms after Antral Pulmonary Vein Isolation for Long-Lasting Persistent Atrial Fibrillation. Journal of the American College of

Cardiology. 2009, 53, 782–9.

22. Dixit, S.; Lin, D.; Frankel, D. S.; Marchlinski, F. E. Catheter Ablation for Persistent Atrial Fibrillation: Antral Pulmonary Vein Isolation and Elimination of Nonpulmonary Vein Triggers Are Sufficient. Circulation: Arrhythmia and

Electrophysiology. 2012, 5, 1216–1223.

23. Verma, A.; Mantovan, R.; Macle, L.; Martino, G. De; Chen, J.; Morillo, C. a; Novak, P.; Calzolari, V.; Guerra, P. G.; Nair, G.; Torrecilla, E. G.; Khaykin, Y. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): A Randomized, Multicentre, International Trial. European heart journal. 2010, 31, 1344–56.

24. Narayan, S. M.; Wright, M.; Derval, N.; Jadidi, A.; Forclaz, A.; Nault, I.; Miyazaki, S.; Sacher, F.; Bordachar, P.; Clémenty, J.; Jaïs, P.; Haïssaguerre, M.; Hocini, M. Classifying Fractionated Electrograms in Human Atrial Fibrillation Using Monophasic Action Potentials and Activation Mapping: Evidence for Localized Drivers, Rate Acceleration, and Nonlocal Signal Etiologies. Heart

rhythm�: the official journal of the Heart Rhythm Society. 2011, 8, 244–53.

ACCEPTED


18

25. Lau, D. H.; Maesen, B.; Zeemering, S.; Verheule, S.; Crijns, H. J.; Schotten, U. Stability of Complex Fractionated Atrial Electrograms:: A Systematic Review. Journal of cardiovascular electrophysiology. 2012, 980–987.

26. Verma, A. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial. ESC Congress. 2014, 2014.

27. Haïssaguerre, M.; Jaïs, P.; Shah, D. C.; Takahashi, A.; Hocini, M.; Quiniou, G.; Garrigue, S.; Mouroux, A. Le; Métayer, P. Le; Clémenty, J. Spontaneous Initiation of Atrial Fibrillation by Ectopic Beats Originating in the Pulmonary Veins. The New England journal of medicine. 1998, 339, 659–666.

28. Calkins, H.; Kuck, K. H.; Cappato, R.; Brugada, J.; Camm, a J.; Chen, S.-A.; Crijns, H. J. G.; Damiano, R. J.; Davies, D. W.; DiMarco, J.; Edgerton, J.; Ellenbogen, K.; Ezekowitz, M. D.; Haines, D. E.; Haissaguerre, M.; Hindricks, G.; Iesaka, Y.; Jackman, W.; Jalife, J.; Jais, P.; Kalman, J.; Keane, D.; Kim, Y.-H.; Kirchhof, P.; Klein, G.; Kottkamp, H.; Kumagai, K.; Lindsay, B. D.; Mansour, M.; Marchlinski, F. E.; McCarthy, P. M.; Mont, J. L.; Morady, F.; Nademanee, K.; Nakagawa, H.; Natale, A.; Nattel, S.; Packer, D. L.; Pappone, C.; Prystowsky, E.; Raviele, A.; Reddy, V.; Ruskin, J. N.; Shemin, R. J.; Tsao, H.-M.; Wilber, D. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-Up, Definitions, Endpoints, and Research Trial Design. Europace�: European pacing,

arrhythmias, and cardiac electrophysiology�: journal of the working groups

on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the

European Society of Cardiology. 2012, 14, 528–606.

29. Herweg, B.; Kowalski, M.; Steinberg, J. S. Termination of Persistent Atrial Fibrillation Resistant to Cardioversion by a Single Radiofrequency Application. Pacing and clinical electrophysiology�: PACE. 2003, 26, 1420–1423.

30. Kuck, K. GAP-AF. EP Europace. 2013, 15.

31. Pratola, C.; Baldo, E.; Notarstefano, P.; Toselli, T.; Ferrari, R. Radiofrequency Ablation of Atrial Fibrillation: Is the Persistence of All Intraprocedural Targets Necessary for Long-Term Maintenance of Sinus Rhythm? Circulation. 2008, 117, 136–143.

32. Jiang, R.-H.; Po, S. S.; Tung, R.; Liu, Q.; Sheng, X.; Zhang, Z.-W.; Sun, Y.-X.; Yu, L.; Zhang, P.; Fu, G.-S.; Jiang, C.-Y. Incidence of Pulmonary Vein Conduction Recovery in Patients without Clinical Recurrence after Ablation of Paroxysmal Atrial Fibrillation: Mechanistic Implications. Heart rhythm�: the official

journal of the Heart Rhythm Society. 2014, 11, 969–76.

33. Oral, H.; Chugh, A.; Good, E.; Igic, P.; Elmouchi, D.; Tschopp, D. R.; Reich, S. S.; Bogun, F.; Pelosi, F.; Morady, F. Randomized Comparison of Encircling and

ACCEPTED


19

Nonencircling Left Atrial Ablation for Chronic Atrial Fibrillation. Heart Rhythm. 2005, 2, 1165–1172.

34. Sauer, W. H.; Alonso, C.; Zado, E.; Cooper, J. M.; Lin, D.; Dixit, S.; Russo, A.; Verdino, R.; Ji, S.; Gerstenfeld, E. P.; Callans, D. J.; Marchlinski, F. E. Atrioventricular Nodal Reentrant Tachycardia in Patients Referred for Atrial Fibrillation Ablation: Response to Ablation That Incorporates Slow-Pathway Modification. Circulation. 2006, 114, 191–195.

35. Lin, W. S.; Tai, C. T.; Hsieh, M. H.; Tsai, C. F.; Lin, Y. K.; Tsao, H. M.; Huang, J. L.; Yu, W. C.; Yang, S. P.; Ding, Y. a.; Chang, M. S.; Chen, S. a. Catheter Ablation of Paroxysmal Atrial Fibrillation Initiated by Non-Pulmonary Vein Ectopy. Circulation. 2003, 107, 3176–3183.

36. Lalani, G. G.; Schricker, A.; Gibson, M.; Rostamian, A.; Krummen, D. E.; Narayan, S. M. Atrial Conduction Slows Immediately before the Onset of Human Atrial Fibrillation: A Bi-Atrial Contact Mapping Study of Transitions to Atrial Fibrillation. Journal of the American College of Cardiology. 2012, 59, 595–606.

37. Narayan, S. M.; Franz, M. R.; Clopton, P.; Pruvot, E. J.; Krummen, D. E. Repolarization Alternans Reveals Vulnerability to Human Atrial Fibrillation. Circulation. 2011, 123, 2922–30.

38. Schricker, A. A.; Lalani, G. G.; Krummen, D. E.; Rappel, W.-J.; Narayan, S. M. Human Atrial Fibrillation Initiates via Organized rather than Disorganized Mechanisms. Circulation. Arrhythmia and electrophysiology. 2014, 7, 816–24.

39. Igarashi, T.; Finet, J. E.; Takeuchi, A.; Fujino, Y.; Strom, M.; Greener, I. D.; Rosenbaum, D. S.; Donahue, J. K. Connexin Gene Transfer Preserves Conduction Velocity and Prevents Atrial Fibrillation. Circulation. 2012, 125, 216–25.

40. Jalife, J. Mechanisms of Persistent Atrial Fibrillation. Current opinion in

cardiology. 2014, 29, 20–27.

41. Jalife, J. Déjà vu in the Theories of Atrial Fibrillation Dynamics. Cardiovascular

research. 2011, 89, 766–75.

42. Schotten, U.; Verheule, S.; Kirchhof, P.; Goette, A. Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal. Physiological …. 2011, 91, 265–325.

43. Moe, G. K.; Rheinboldt, W. C.; Abildskov, J. A. A COMPUTER MODEL OF ATRIAL FIBRILLATION. American heart journal. 1964, 67, 200–20.

44. Abildskov, J. A. Additions to the Wavelet Hypothesis of Cardiac Fibrillation. Journal of cardiovascular electrophysiology. 1994, 5, 553–9.

ACCEPTED


20

45. Carrick, R. T.; Benson, B.; Habel, N.; Bates, O. R. J.; Bates, J. H. T.; Spector, P. S. Ablation of Multiwavelet Re-Entry Guided by Circuit-Density and Distribution: Maximizing the Probability of Circuit Annihilation. Circulation. Arrhythmia and

electrophysiology. 2013, 6, 1229–35.

46. Moe, G. K.; Abildskov, J. A. Atrial Fibrillation as a Self-Sustaining Arrhythmia Independent of Focal Discharge. American heart journal. 1959.

47. Allessie, M. A.; Groot, N. M. S. de; Houben, R. P. M.; Schotten, U.; Boersma, E.; Smeets, J. L.; Crijns, H. J. Electropathological Substrate of Long-Standing Persistent Atrial Fibrillation in Patients with Structural Heart Disease: Longitudinal Dissociation. Circulation. Arrhythmia and electrophysiology. 2010, 3, 606–615.

48. Eckstein, J.; Maesen, B.; Linz, D.; Zeemering, S.; Hunnik, A. van; Verheule, S.; Allessie, M.; Schotten, U. Time Course and Mechanisms of Endo-Epicardial Electrical Dissociation during Atrial Fibrillation in the Goat. Cardiovascular

research. 2011, 89, 816–24.

49. Niu, G.; Scherlag, B. J.; Lu, Z.; Ghias, M.; Zhang, Y.; Patterson, E.; Dasari, T. W.; Zacharias, S.; Lazzara, R.; Jackman, W. M.; Po, S. S. An Acute Experimental Model Demonstrating 2 Different Forms of Sustained Atrial Tachyarrhythmias. Circulation. Arrhythmia and electrophysiology. 2009, 2, 384–92.

50. Gerstenfeld, E. P.; Sahakian, a. V.; Swiryn, S. Evidence for Transient Linking of Atrial Excitation during Atrial Fibrillation in Humans. Circulation. 1992, 86, 375–382.

51. Ng, J.; Gordon, D.; Passman, R. S.; Knight, B. P.; Arora, R.; Goldberger, J. J. Electrogram Morphology Recurrence Patterns during Atrial Fibrillation. Heart

rhythm�: the official journal of the Heart Rhythm Society. 2014.

52. Atienza, F.; Almendral, J.; Jalife, J.; Zlochiver, S.; Ploutz-Snyder, R.; Torrecilla, E. G.; Arenal, A.; Kalifa, J.; Fernández-Avilés, F.; Berenfeld, O. Real-Time Dominant Frequency Mapping and Ablation of Dominant Frequency Sites in Atrial Fibrillation with Left-to-Right Frequency Gradients Predicts Long-Term Maintenance of Sinus Rhythm. Heart rhythm�: the official journal of the Heart

Rhythm Society. 2009, 6, 33–40.

53. Pandit, S. V.; Jalife, J. Rotors and the Dynamics of Cardiac Fibrillation. Circulation Research. 2013, 112, 849–862.

54. Ghoraani, B.; Dalvi, R.; Gizurarson, S.; Das, M.; Ha, A.; Suszko, A.; Krishnan, S.; Chauhan, V. S. Localized Rotational Activation in the Left Atrium during Human Atrial Fibrillation: Relationship to Complex Fractionated Atrial Electrograms and Low-Voltage Zones. Heart rhythm�: the official journal of

the Heart Rhythm Society. 2013, 10, 1830–1838.

ACCEPTED


21

55. Lin, Y.-J.; Lo, M.-T.; Lin, C.; Chang, S.-L.; Lo, L.-W.; Hu, Y.-F.; Hsieh, W.-H.; Chang, H.-Y.; Lin, W.-Y.; Chung, F.-P.; Liao, J.-N.; Chen, Y.-Y.; Hanafy, D.; Huang, N. E.; Chen, S.-A. Prevalence, Characteristics, Mapping, and Catheter Ablation of Potential Rotors in Nonparoxysmal Atrial Fibrillation. Circulation.

Arrhythmia and electrophysiology. 2013, 6, 851–8.

56. Wagoner, D. R. Van; Piccini, J. P.; Albert, C. M.; Anderson, M. E.; Benjamin, E. J.; Brundel, B.; Califf, R. M.; Calkins, H.; Chen, P.-S.; Chiamvimonvat, N.; Darbar, D.; Eckhardt, L.; Ellinor, P. T.; Exner, D. V.; Fogel, R. I.; Gillis, A. M.; Healey, J.; Hohnloser, S. H.; Kamel, H.; Lathrop, D. a.; Lip, G. Y. H.; Mehra, R.; Narayan, S. M.; Olgin, J.; Packer, D.; Peters, N. S.; Roden, D. M.; Ross, H. M.; Sheldon, R.; Wehrens, X. H. T. Progress towards the Prevention and Treatment of Atrial Fibrillation: A Summary of the Heart Rhythm Society Research Forum on the Treatment and Prevention of Atrial Fibrillation, Washington, D.C., December 9-10, 2013. Heart Rhythm. 2014.

57. Narayan, S. M.; Baykaner, T.; Clopton, P.; Schricker, A.; Lalani, G. G.; Krummen, D. E.; Shivkumar, K.; Miller, J. M. Ablation of Rotor and Focal Sources Reduces Late Recurrence of Atrial Fibrillation Compared With Trigger Ablation Alone: Extended Follow-Up of the CONFIRM Trial (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulat. Journal of the American College of Cardiology. 2014, 63, 1761–8.

58. Shivkumar, K.; Ellenbogen, K. A.; Hummel John, D.; Miller, J. M.; Steinberg, J. S. Acute Termination of Human Atrial Fibrillation by Identification and Catheter Ablation of Localized Rotors and Sources�: First Multicenter Experience of Focal Impulse and Rotor Modulation ( FIRM ) Ablation. Journal of

cardiovascular electrophysiology. 2012, 23, 1277–1285.

59. Swarup, V.; Baykaner, T.; Rostamian, A.; Daubert, J.; Hummel, J.; Krummen, D. E.; Trikha, R.; Miller, J. M.; Tomassoni, G.; Narayan, S. M. Stability of Rotors and Focal Sources for Human Atrial Fibrillation�: Focal Impulse and Rotor Mapping (FIRM) of AF Sources and Fibrillatory Conduction. Journal of

cardiovascular electrophysiology. 2014, 1–23.

60. Miller, J. M.; Kowal, R. C.; Swarup, V.; Daubert, J. P.; Daoud, E. G.; Day, J. D.; Ellenbogen, K. A.; Hummel, J. D.; Baykaner, T.; Krummen, D. E.; Narayan, S. M.; Reddy, V. Y.; Shivkumar, K.; Steinberg, J. S.; Wheelan, K. R. Initial Independent Outcomes from Focal Impulse and Rotor Modulation Ablation for Atrial Fibrillation: Multicenter FIRM Registry. Journal of cardiovascular

electrophysiology. 2014, 25, 921–929.

61. Rivard, L.; Hocini, M.; Rostock, T.; Cauchemez, B.; Forclaz, A.; Jadidi, A. S.; Linton, N.; Nault, I.; Miyazaki, S.; Liu, X.; Xhaet, O.; Shah, A.; Sacher, F.; Derval, N.; Jaïs, P.; Khairy, P.; Macle, L.; Nattel, S.; Willems, S.; Haïssaguerre, M. Improved Outcome Following Restoration of Sinus Rhythm prior to Catheter

ACCEPTED


22

Ablation of Persistent Atrial Fibrillation: A Comparative Multicenter Study. Heart Rhythm. 2012, 9, 1025–1030.

62. Sarmast, F.; Kolli, A.; Zaitsev, A.; Parisian, K.; Dhamoon, A. S.; Guha, P. K.; Warren, M.; Anumonwo, J. M. B.; Taffet, S. M.; Berenfeld, O.; Jalife, J. Cholinergic Atrial Fibrillation: I(K,ACh) Gradients Determine Unequal Left/right Atrial Frequencies and Rotor Dynamics. Cardiovascular research. 2003, 59, 863–73.

63. Linz, D.; Ukena, C.; Mahfoud, F.; Neuberger, H. R.; Böhm, M. Atrial Autonomic Innervation: A Target for Interventional Antiarrhythmic Therapy? Journal of

the American College of Cardiology. 2014, 63, 215–224.

64. Katritsis, D. G.; Pokushalov, E.; Romanov, A.; Giazitzoglou, E.; Siontis, G. C. M.; Po, S. S.; Camm, a. J.; Ioannidis, J. P. a Autonomic Denervation Added to Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation: A Randomized Clinical Trial. Journal of the American College of Cardiology. 2013, 62, 2318–2325.

65. Marrouche, N. F.; Wilber, D.; Hindricks, G.; Jais, P.; Akoum, N.; Marchlinski, F.; Kholmovski, E.; Burgon, N.; Hu, N.; Mont, L.; Deneke, T.; Duytschaever, M.; Neumann, T.; Mansour, M.; Mahnkopf, C.; Herweg, B.; Daoud, E.; Wissner, E.; Bansmann, P.; Brachmann, J. Association of Atrial Tissue Fibrosis Identified by Delayed Enhancement MRI and Atrial Fibrillation Catheter Ablation: The DECAAF Study. Jama. 2014, 311, 498–506.

66. Spragg, D. D.; Khurram, I.; Zimmerman, S. L.; Yarmohammadi, H.; Barcelon, B.; Needleman, M.; Edwards, D.; Marine, J. E.; Calkins, H.; Nazarian, S. Initial Experience with Magnetic Resonance Imaging of Atrial Scar and Co-Registration with Electroanatomic Voltage Mapping during Atrial Fibrillation: Success and Limitations. Heart Rhythm. 2012, 9, 2003–2009.

67. Sramko, M.; Peichl, P.; Wichterle, D.; Tintera, J.; Weichet, J.; Maxian, R.; Pasnisinova, S.; Kockova, R.; Kautzner, J. Clinical Value of Assessment of Left Atrial Late Gadolinium Enhancement in Patients Undergoing Ablation of Atrial Fi Brillation. International Journal of Cardiology. 2015, 179, 351–357.

68. Zaman, J. A. B.; Peters, N. S. The Rotor Revolution: Conduction at the Eye of the Storm in Atrial Fibrillation. Circulation: Arrhythmia and Electrophysiology. 2014, 7, 1230–1236.

69. Camm, A. J.; Lip, G. Y. H.; Caterina, R. De; Savelieva, I.; Atar, D.; Hohnloser, S. H.; Hindricks, G.; Kirchhof, P. 2012 Focused Update of the ESC Guidelines for the Management of Atrial Fibrillation: An Update of the 2010 ESC Guidelines for the Management of Atrial Fibrillation. Developed with the Special Contribution of the European Heart Rhythm Association. European heart

journal. 2012, 33, 2719–47.

ACCEPTED


23

70. Platonov, P. G.; Mitrofanova, L. B.; Orshanskaya, V.; Ho, S. Y. Structural Abnormalities in Atrial Walls Are Associated with Presence and Persistency of Atrial Fibrillation but Not with Age. Journal of the American College of

Cardiology. 2011, 58, 2225–32.

71. Nademanee, K.; Amnueypol, M.; Lee, F.; Drew, C. M.; Suwannasri, W.; Schwab, M. C. Bene Fi Ts and Risks of Catheter Ablation in Elderly Patients with Atrial Fi Brillation. Heart Rhythm. 2015, 12, 44–51.

72. Stepanyan, G.; Gerstenfeld, E. P. Atrial Fibrillation Ablation in Octogenarians: Where Do We Stand? Current cardiology reports. 2013, 15, 406.

73. Piccini, J. P.; Sinner, M. F.; Greiner, M. a.; Hammill, B. G.; Fontes, J. D.; Daubert, J. P.; Ellinor, P. T.; Hernandez, A. F.; Walkey, A. J.; Heckbert, S. R.; Benjamin, E. J.; Curtis, L. H. Outcomes of Medicare Beneficiaries Undergoing Catheter Ablation for Atrial Fibrillation. Circulation. 2012, 126, 2200–2207.

74. Heist, E. K.; Chalhoub, F.; Barrett, C.; Danik, S.; Ruskin, J. N.; Mansour, M. Predictors of Atrial Fibrillation Termination and Clinical Success of Catheter Ablation of Persistent Atrial Fibrillation. American Journal of Cardiology. 2012, 110, 545–551.

75. Baykaner, T.; Lalani, G. G.; Schricker, A.; Krummen, D. E.; Narayan, S. M. Mapping and Ablating Stable Sources for Atrial Fibrillation: Summary of the Literature on Focal Impulse and Rotor Modulation (FIRM). Journal of

interventional cardiac electrophysiology�: an international journal of

arrhythmias and pacing. 2014.

76. Abed, H. S.; Samuel, C. S.; Lau, D. H.; Kelly, D. J.; Royce, S. G.; Alasady, M.; Mahajan, R.; Kuklik, P.; Zhang, Y.; Brooks, A. G.; Nelson, A. J.; Worthley, S. G.; Abhayaratna, W. P.; Kalman, J. M.; Wittert, G. a; Sanders, P. Obesity Results in Progressive Atrial Structural and Electrical Remodeling: Implications for Atrial Fibrillation. Heart rhythm�: the official journal of the Heart Rhythm Society. 2013, 10, 90–100.

77. Pathak, R. K.; Middeldorp, M. E.; Lau, D. H.; Mehta, A. B.; Mahajan, R.; Twomey, D.; Alasady, M.; Hanley, L.; Antic, N. A.; McEvoy, D.; Kalman, J. M.; Abhayaratna, W. P.; Sanders, P. Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation The ARREST-AF Cohort Study. Journal of the American College of Cardiology. 2014, 64, 2222–2231.

78. Baykaner, T.; Clopton, P.; Lalani, G. G.; Schricker, A. A.; Krummen, D. E.; Narayan, S. M. Targeted Ablation at Stable Atrial Fibrillation Sources Improves Success over Conventional Ablation in High-Risk Patients: A Substudy of the CONFIRM Trial. The Canadian journal of cardiology. 2013, 29, 1218–1226.

ACCEPTED


24

79. Kottkamp, H. Human Atrial Fibrillation Substrate: Towards a Specific Fibrotic Atrial Cardiomyopathy. European heart journal. 2013, 34, 2731–2738.

80. McGann, C.; Akoum, N.; Patel, A.; Kholmovski, E.; Revelo, P.; Damal, K.; Wilson, B.; Cates, J.; Harrison, A.; Ranjan, R.; Burgon, N. S.; Greene, T.; Kim, D.; Dibella, E. V. R.; Parker, D.; Macleod, R. S.; Marrouche, N. F. Atrial Fibrillation Ablation Outcome Is Predicted by Left Atrial Remodeling on MRI. Circulation.

Arrhythmia and electrophysiology. 2013, 7, 23–30.

81. Woods, C. E.; Olgin, J. Atrial Fibrillation Therapy Now and in the Future: Drugs, Biologicals, and Ablation. Circulation research. 2014, 114, 1532–46.

82. Venetucci, L.; Denegri, M.; Napolitano, C.; Priori, S. G. Inherited Calcium Channelopathies in the Pathophysiology of Arrhythmias. Nature reviews.

Cardiology. 2012, 9, 561–575.

83. Koskinas, K. C.; Fragakis, N.; Katritsis, D.; Skeberis, V.; Vassilikos, V. Ranolazine Enhances the Efficacy of Amiodarone for Conversion of Recent-Onset Atrial Fibrillation. Europace�: European pacing, arrhythmias, and cardiac

electrophysiology�: journal of the working groups on cardiac pacing,

arrhythmias, and cardiac cellular electrophysiology of the European Society of

Cardiology. 2014, 16, 973–9.

84. Narayan, S. M.; Krummen, D. E.; Donsky, A.; Swarup, V.; Tomassoni, G.; Miller, J. M. Treatment Of Paroxysmal Atrial Fibrillation By Targeted Elimination Of Stable Rotors And Focal Sources Without Pulmonary Vein Isolation: The Precise Rotor Elimination Without Concomitant Pulmonary Vein Isolation For Subsequent Elimination Of PAF (PRECISE). Heart Rhythm. 2013, LB01–05.

85. Tilz, R. R.; Rillig, A.; Thum, A.-M.; Arya, A.; Wohlmuth, P.; Metzner, A.; Mathew, S.; Yoshiga, Y.; Wissner, E.; Kuck, K.-H.; Ouyang, F. Catheter Ablation of Long-Standing Persistent Atrial Fibrillation: 5-Year Outcomes of the Hamburg Sequential Ablation Strategy. Journal of the American College of

Cardiology. 2012, 60, 1921–9.

86. Narayan, S. M.; Baykaner, T.; Clopton, P.; Schricker, A.; Lalani, G.; Krummen, D. E.; Shivkumar, K.; Miller, J. M. Ablation of Rotor and Focal Sources Reduces Late Recurrence of Atrial Fibrillation Compared to Trigger Ablation Alone. Journal of the American College of Cardiology. 2014, 63, 1761–1768.

87. Nishida, K.; Datino, T.; Macle, L.; Nattel, S. Atrial Fibrillation Ablation. Journal

of the American College of Cardiology. 2014, 64, 823–831.

88. Narayan, S. M.; Jalife, J. Rotors Have Been Demonstrated to Drive Human Atrial Fibrillation. J Physiol. 2014, 15, 3163–3166.

89. Opolski, G.; Torbicki, A.; Kosior, D. A.; Szulc, M.; Wozakowska-Kapłon, B.; Kołodziej, P.; Achremczyk, P. Rate Control vs Rhythm Control in Patients with

ACCEPTED


25

Nonvalvular Persistent Atrial Fibrillation: The Results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest. 2004, 126, 476–486.

90. Talajic, M.; Khairy, P.; Levesque, S.; Connolly, S. J.; Dorian, P.; Dubuc, M.; Guerra, P. G.; Hohnloser, S. H.; Lee, K. L.; Macle, L.; Nattel, S.; Pedersen, O. D.; Stevenson, L. W.; Thibault, B.; Waldo, A. L.; Wyse, D. G.; Roy, D. Maintenance of Sinus Rhythm and Survival in Patients With Heart Failure and Atrial Fibrillation. Journal of the American College of Cardiology. 2010, 55, 1796–1802.

ACCEPTED


26

Figure legends:

Figure 1.

Current strategies and evolution of current clinical ablation. Multiwavelet theory

(A) which had excellent results with Cox-Maze (B), providing evidence either for

atrial compartmentalisation or inadvertent source modification. The PVs were

identified as the first trigger of human AF (D) and isolation of them has led to

success in many paroxysmal patients. However the non-responders or those

with advanced disease will benefit from more detailed study (E) and ablation

(F). From 87

Figure 2.

Triggers Initiate AF via Transitional Organized Mechanisms. A) Isochronal

activation map shows a sinus beat commencing low in the sinus node (red),

followed by (B) a spontaneous premature atrial complex from the anterolateral

RA causing slowed conduction in the inferior RA. A septal right atrial beat in (C)

encounters late-activated tissue in the low septal RA, cannot activate clockwise

and activates in the opposite direction to form a spiral wave. D) This transitional

mechanism was conserved in 3 initiations in the same patient (star represents

trigger, circle represents rotor core). From 38

ACCEPTED


27

Figure 3.

Ablation at Localized Sources for Human AF.

A) Long term data showing

superior freedom from AF when adding FIRM over conventional ablation

alone. B). FIRM map showing left atrial rotor surrounded by complex

fibrillatory dynamics, where limited focal ablation eliminated AF acutely and

on long-term follow-up. C) Inferred image from non-invasive body surface

mapping, indicating a phase map showing a left atrial rotor with simple

dynamics and minimal surrounding fibrillatory activity. From 15,57,88

Table 1. Summary of antiarrhythmic drugs (AAD) comparison with catheter ablation for AF now and in the future for first and second line therapeutic strategy.

ACCEPTED


Table 1. Summary of antiarrhythmic drugs (AAD) comparison with catheter ablation

for AF now and in the future for first and second line therapeutic strategy.

Patient

group

Rhythm

strategy

AAD AF Ablation –

current

AF Ablation –

future

Drug naïve patient

(First line ablation)

Equivalent to rate control (AFFIRM1, RACE I2, HOT-CAFÉ89, AF-in-CHF90)

Superior to AAD (RAAFT-29) or non-

inferior (MANTRA-PAF10)

Likely superior to AAD if targeting physiologically mapped AF sources (e.g. FIRM86).

Failure of drugs

(Second line

ablation)

Rate control adopted ‘permanent (accepted) AF’

Superior to AAD (SARA6, STOP-AF8, Thermocool AF7)

Possible reduction of AF burden. ‘Cure’ less

likely Due to more advanced disease

ACCEPTED


ACCEPTED


ACCEPTED


ACCEPTED


Date post:	14-May-2023
Category:	Documents
Upload:	stanford
View:	1 times
Download:	0 times

New mechanism-based approaches to ablating persistent AF - will drug therapy soon be obsolete?

Documents