Circulation: Arrhythmia and Electrophysiology. 2008;1:2-5
doi: 10.1161/CIRCEP.108.764233
The Substrate Maintaining Persistent Atrial Fibrillation
Michel Haïssaguerre, MD,
Matthew Wright, MBBS, PhD,
Mélèze Hocini, MD and
Pierre Jaïs, MD
From the Hôpital Cardiologique du Haut-Lévêque and the Université Victor Segalen, Bordeaux II, Bordeaux, France.
Correspondence: Correspondence to Service de Rythmologie, Hôpital Cardiologique du Haut-Lévêque, Avenue de Magellan, 33604 Bordeaux-Pessac, France. E-mail jacques.clementy{at}pu.u-bordeaux2.fr
Key Words: Editorials ablation fibrillation arrhythmias mapping
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Introduction
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Complex fractionated atrial electrogram (CFAE) ablation is one
successful approach for treating patients with persistent atrial
fibrillation (AF), along with strategies that incorporate pulmonary
vein isolation and linear lesions. In this issue of
Circulation: Arrhythmia and Electrophysiology, Oral et al
1 investigate the
effect of right atrial CFAE focused ablation in patients with
long-lasting persistent fibrillation. All patients had CFAE
ablation in the left atrium and coronary sinus, and patients
who did not convert to either sinus rhythm or atrial tachycardia
were randomized to either additional right atrial CFAE ablation
or to no further ablation. Patients were followed up for more
than 1 year with similar outcomes in both groups, which suggests
that right atrial CFAE ablation has no incremental benefit to
targeting CFAE in the left atrium in persistent AF. Oral et
al
1 do acknowledge some limitations in their study design, which
may have given a false-negative result.
Page 6
Does the right atrial substrate play an important role in persistent AF, and how do we distinguish patients in whom the right atrium needs to be targeted as part of a catheter ablation strategy from those in whom the right atrium is unimportant?
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Does CFAE Represent the Atrial Substrate?
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The Heart Rhythm Society/European Heart Rhythm Association/European
Cardiac Arrhythmia Society expert consensus document
2 on catheter
and surgical ablation of AF suggests that areas with CFAEs potentially
represent AF substrate sites, ie, the atrial, venous, and ganglionic
tissue that is critical in perpetuating or "driving" AF. Is
this widely held assumption that CFAEs are related to the substrate
correct? CFAEs are defined as electrograms displaying >2
deflections that are fractionated or have a short cycle length
<120 ms,
3 in their maximal form giving continuous electrical
activity.
4 Twenty years ago, such split potentials were observed
after premature stimuli in patients with or without AF, and
the split potentials indicated local slow conduction.
5 That
split potentials are caused by nonuniform or slow atrial propagation,
resulting in different activations between myocardial fibers
sensed by the recording electrode, is supported by multiple
prior studies, notably those by Spach and Allessie. Underlying
myocardial fibers have poor electrical coupling and can be separated
by fibrous tissue, causing activation to spread into a maze
of micropathways. Fractionation is critically dependent on both
the direction of wavefront progression and its cycle length.
6,7 In animal experiments, Kalifa et al
8 demonstrated that the fractionation
was located at the boundary of high-frequency sources because
of wavebreak related to local tissue architecture. In humans,
high-density mapping during AF demonstrated that the formation
of CFAE was preceded in 91% of mapped sites by shortening of
the atrial cycle length, which further supports the key role
that cycle length plays in the generation of CFAE.
9 In practice,
diffuse fractionation will accompany short AF cycle length (AFCL)
(commonly

150 ms in persistent AF); more limited fractionation
will occur in paroxysmal AF because of the longer AFCL (typically
>170 ms); and little fractionation is observed when AFCL
is long.
Therefore, the mechanism by which CFAE ablation can prolong AFCL or terminate AF is unknown. On the basis of their physiopathology, we may hypothesize that some fractionated areas act like a reservoir of microreentrant activities, continually refueling the fibrillatory process.
In animal experiments, the AF substrate involves wandering wavelets, macroreentries, and focal sources. In humans, no study has demonstrated the feasibility of individually discriminating these mechanisms. Noncontact mapping, allowing simultaneous acquisition of beat-to-beat activity in the whole chamber, is theoretically the ideal tool to map AF; however, so far it has not proved practical in the clinical setting. Studies that use frequency domain analysis are limited by methodological issues, notably with regard to fractionation, and so far they also have not been helpful in persistent AF. Time domain analysis is difficult because of irregularity of cycle, definition of early versus late activation, and ambiguity in ascribing local activation during fractionated activity. In addition, a perpetuating source may act intermittently or may be rendered "invisible" when the surrounding tissue has been rendered refractory by other coexisting sources (see below).
Identification of AF sources has been reported to be feasible with high-density mapping during specific conditions, either perioperatively10 or during organized AF.11 These studies have demonstrated atrial activation spreading from focal point sources or from small areas harboring localized reentry, displaying fractionated or nonfractionated electrograms at the source location.
Indirectly, by evaluating the impact of CFAE on AFCL, we have learned that all anatomic areas are not equal in their contribution to maintenance of AF. Regions that have the greatest influence are the pulmonary veins, the base of the left atrial appendage, and the inferior left atrium–coronary sinus interface. Interestingly, these regions have the common feature of being annexed to the main body of the left atrium by numerous connections. Their arrhythmogenic potential may be due to local structural discontinuity or to dynamic "ping-pong" interaction between the 2 structures that continuously refuel the AF process. In support of this hypothesis, it is striking that isolation of the pulmonary veins often leads to cessation of pulmonary vein tachycardia, distal to the isolation site, which suggests that the connection to the left atrium was necessary for the continuation of venous firing, and vice versa.
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Fibrillatory Cycle Length as a Marker of Substrate Burden
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It is well known that the extent of AF substrate correlates
with the duration of AF and the volume of the left atrium. Furthermore,
AFCL, a measurement of fibrillation rate, strongly correlates
with acute termination of AF both by catheter ablation and pharmacological
or electrical cardioversion and hence can be used as a marker
of AF substrate burden. That AFCL is not simply a surrogate
of the local refractory period is evidenced by the prolongation
of AFCL at remote sites during ablation. Additional insights
have been gained by computer modeling of AF. In a model based
on the assumption that AF is due to multiple sources, AFCL progressively
decreases with the addition of more focal sources, up to a threshold.
12 In this computer simulation, although all sources are continually
firing, not all of them can be "seen" at any given time, and
thus several snapshots in time are necessary to be able to visualize
and map all of the sources (
Figure 1). Initially, AFCL changes
only minimally, as another source can take over from the one
that has been ablated. Then, as more sources are eliminated,
the AF becomes more organized, and the AFCL prolongs to the
point of conversion to either sinus rhythm or atrial tachycardia,
when only 1 or 2 sources are present (
Figure 2). This correlates
well with what we have observed during catheter ablation of
persistent AF. The shorter the baseline AFCL, the more ablation
is required to prolong the AFCL and to reach the critical point
at which conversion to either sinus rhythm or atrial tachycardia
occurs, typically around 200 ms.

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Figure 1. Computer simulation of AF. With the use of a multiple-source model of AF, with 8 active sources, the local activation is visualized. Transmembrane potential is color coded. Tissue in the resting state is coded blue and activated tissue in yellow/orange. The 8 sources have different periodicities, and at any one time only 3 sources are seen because of local tissue refractoriness, even though all are continually active. A, Anterior and posterior views of the right and left atrium, with the location of the sources marked. B through D, Different snapshots in time showing the different active sources at that instant.12
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Figure 2. Effect of extinguishing sources on AFCL. In the computer model, as the number of sources decreases, the AFCL progressively increases, which only becomes significant when fewer than 4 sources remain. As further sources are extinguished, the AF organizes into an atrial tachycardia.
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Multiple Sources as a Major Mechanism in Human AF
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The evidence from catheter ablation supports the hypothesis
that AF involves multiple sources.
Source is used in a broad
sense to indicate a localized origin of atrial wavefronts, without
inferring the mechanism or size of the source. Work in human
electrophysiology has confirmed the dominance of pulmonary vein
sources in paroxysmal AF. In persistent AF, the role of sources
is less clear. Studies by Oral et al
1 and others
3 demonstrate
that multiple-point ablation targeting CFAE leads to AF termination.
The latter finding is not consistent with the wandering wavelet
mechanism, given that point ablation should increase the number
of wavelets by creating multiple anchoring points, thus worsening
AF.
Finally, the critical AFCL at which conversion of AF occurs is strikingly similar to the cycle of the subsequent atrial tachycardia, mimicking a progressive extinction of sources. In a few patients, however, AF cannot be organized by ablation, which suggests incessantly changing activation sequences that could be due to wandering wavelets.
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The Role of the Right Atrium
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Early work investigated the utility of right atrial linear lesions,
with or without additional left atrial linear lesions, with
only modest success in patients with either paroxysmal or persistent
AF. In the stepwise approach in which multiple atrial structures
are targeted, termination occurred in 84% of patients during
left atrial ablation. Notably, the order of ablation targets
(pulmonary veins, CFAE, coronary sinus, and linear lesions)
was shown to be irrelevant, which suggests that all of the targets
contributed to the maintenance of AF. In most patients, the
AFCL prolongation in the left atrium was mirrored by a similar
prolongation of AFCL in the right atrium, which clearly indicates
that the right atrium was driven from the left atrium. In patients
without termination in the left atrium, AFCL was less prolonged
in the right atrium, resulting in a right-to-left frequency
gradient and suggesting that the right atrium harbored the driving
activity. This hypothesis was confirmed by the fact that right
atrial ablation resulted in termination in most of these patients,
whereas it was found that the right atrium was involved in 20%
of all cases of persistent AF (M. Hocini, unpublished observations).
An earlier study demonstrated that AF that originated solely from the right atrium could be effectively ablated by targeting the crista terminalis.13 The long-term success rate in these patients was 85%, but they only constituted 3% of the screened population. This relatively low prevalence of patients with right atrial drivers may explain why Oral et al1 were unable to demonstrate any benefit of right atrial ablation because of a limited sample size, as the authors acknowledge.
Therefore, indiscriminate targeting of the right atrium is apparently unnecessary, but in a specific subset of patients and guided by AFCL monitoring in both chambers, targeting of the right atrium is key to termination of AF.
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The Future: Effective Cure of AF With Minimal Ablation
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The circuit in atrioventricular nodal reentrant tachycardia
is still not fully understood; nevertheless, we are able to
effectively treat this arrhythmia. The same is now true for
AF. We may ultimately fail in our quest to fully understand
the mechanisms underlying AF, but we are approaching the end
of this journey, with an effective cure of this complex arrhythmia.
AF ablation success rates with a number of different strategies—pulmonary vein isolation, electrogram-based ablation, and linear lesions—are continually improving. The combination of these approaches has led to unprecedented success in treating persistent AF, particularly when procedural termination of AF is achieved. Such patients have better outcomes than patients without termination, as observed in the study by Oral et al.1 Intuitively, AF termination means that all actively participating elements have been eliminated; in our opinion, this represents the optimal end point. After restoration of sinus rhythm, assessment and completion of pulmonary vein isolation and linear block are necessary to ensure long-term maintenance of sinus rhythm.
This extensive ablation approach is associated with significant alteration of atrial tissue, and although extensive scarring and low-voltage areas result (
40% of left atrial surface), mechanical function is restored. In patients who had no atrial function in AF, restoration of mechanical function is a great improvement, and we can expect it to affect their embolic risk, ventricular function, and quality of life. Nevertheless, we should do better. In addition to improving ablation catheters, further effort should be directed to identifying the sources or other mechanisms that are active in any particular patient, either by refining the present mapping tools or by developing new techniques. One challenge is to decipher CFAEs and link them to the underlying substrate to obtain an effective cure of AF with the minimum degree of ablation in each individual patient.
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Acknowledgments
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Disclosures
None.
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Footnotes
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The opinions expressed in this article are not necessarily those
of the editors or of the American Heart Association.
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Related articles in Circ Arrhythmia Electrophysiol:
- Randomized Evaluation of Right Atrial Ablation After Left Atrial Ablation of Complex Fractionated Atrial Electrograms for Long-Lasting Persistent Atrial Fibrillation
- Hakan Oral, Aman Chugh, Eric Good, Thomas Crawford, Jean F. Sarrazin, Michael Kuhne, Nagib Chalfoun, Darryl Wells, Warangkna Boonyapisit, Nitesh Gadeela, Sundar Sankaran, Ayman Kfahagi, Krit Jongnarangsin, Frank Pelosi, Jr, Frank Bogun, and Fred Morady
Circ Arrhythmia Electrophysiol 2008 1: 6-13.
[Abstract]
[Full Text]