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Complex fractionated atrial electrograms: potential targets for the management of atrial fibrillation

Complex fractionated atrial electrograms are electrophysiological mechanisms that are thought to sustain atrial fibrillation. As such, they represent potentially important therapeutic opportunities for ablation therapy

Emily Irwin
Healthcare writer

Normal heart rhythm, or sinus rhythm, is achieved through the coordinated action of specialised cells in the atria and ventricles, triggered by the electrical activity of the sinus node. Atrial fibrillation (AF) is characterised by uncoordinated atrial activity; transmission of electrical impulses from multiple locations overloads the atrioventricular node resulting in rapid, irregular beating of the heart and impaired blood flow.
Typically, AF is characterised based on the duration of each episode. International guidelines define two or more episodes as recurrent AF; recurrent AF that terminates spontaneously
within seven days as paroxysmal AF; AF that is sustained beyond seven days or requiring pharmacologic or electrical cardioversion to terminate as persistent AF, or long-standing
persistent AF whether continuous AF of greater than one year duration. Permanent AF refers to patients in whom cardioversion has either failed or has not been attempted.[1]
Arrhythmias are not uncommon; an estimated 4.5 million individuals in the EU have paroxysmal or persistent AF,[2] and prevalence increases to almost 10% in men and women aged
over 80 years.[3] Patients with AF face increased risks of heart failure, thrombosis and stroke, and a mortality approximately twice that of individuals with normal sinus rhythm.[4,5,6] For a
succinct overview of atrial fibrillation, the reader is referred to ‘Therapeutic goals of treating  atrial fibrillation’, by Jaap Deckers and Yves van Belle in the 2009 edition of Hospital Healthcare Europe.[5]

Therapeutic management of AF
Management of AF requires knowledge of its presentation and underlying conditions, and focuses on three objectives: controlling the ventricular rate, correcting rhythm disturbance
and preventing thromboembolism.[4]
Pharmacological therapies may be effective for both rate and rhythm control and are typically considered as first-line approaches for the management of AF.[4] However, pharmacological treatments have been associated with high rates of AF recurrence and proarrhythmic sequelae.[7]
As a result, catheter-based ablation, currently considered the second-line approach for AF,[4] is being used increasingly in certain subsets of patients with the aim of achieving a cure.

Electrophysiological mechanisms underlying AF
AF is a complex condition that is thought to be self-perpetuating; chronic or recurrent fibrillatory activation induces progressive electrical and structural remodelling that, in turn, promotes further fibrillatory activation.[8]
The onset and maintenance of AF requires an initiating event, or trigger, and a maintaining mechanism, or substrate.[4 ]Initiating triggers are electrophysiologically well-defined regions of cardiac tissue, located mainly in the pulmonary veins (PV), that represent focal points of electrical activity.[9] Anatomical substrates are more difficult to define, but it has been suggested that complex fractionated atrial electrograms (CFAEs) may correlate with these substrates. CFAEs are thought to define areas of underlying fibrosis or slow conduction – the result of structural remodelling due to high ventricular rates or heart disease – that enable the continuous re-entry or overlapping of fibrillation waves within the same area, thus perpetuating AF.[10] Indeed, data have demonstrated that local CFAE morphology corresponds to areas of non-uniform wave propagation.[11]

Catheter-based ablation for the treatment of AF
Increased understanding of these electrophysiological mechanisms has resulted in the evolution of catheter-based ablation techniques for the treatment of AF. PV isolation by radiofrequency ablation is now considered an important
treatment option for symptomatic recurrent paroxysmal AF, where normal sinus rhythm cannot be maintained with drug therapy alone.[8,12] Indeed, in cases of paroxysmal AF where there is a single point of origin of atrial triggers, PV isolation by radiofrequency ablation is often sufficient to achieve a cure.[9]
However, in patients with persistent or long-standing AF, where extensive atrial fibrosis increases the number of factors driving
the condition, PV isolation alone will not usually achieve a long-term cure.[8] Studies have demonstrated that the extent and locations of left atrial enhancement may be important predictors of ablation success and, in cases of longstanding
AF involving several regions of atrial enhancement, recurrence following ablation is common.[8,12] “CFAE ablation may be considered…as an additional strategy [to PV isolation] in longstanding persistent AF”, advised Dr Mercèdes Nadal, an electrophysiologist at the University of Barcelona, Catalonia, Spain.

Electroanatomical mapping of CFAEs
Since the identification of the mechanisms that trigger and maintain AF, electroanatomical mapping software has been developed to assist electrophysiologists in the accurate  identification and ablation of PV foci and areas of CFAEs. Use of this technology for the visualisation and ablation of CFAEs was first reported in 2004.[10] The investigators in this study used multielectrode catheters and electroanatomical mapping software (CartoXP; Biosense Webster, CA, USA) to record the electrical activity that preceded the onset of AF in 121 patients with refractory AF (57 paroxysmal, 64 chronic). They demonstrated that ablation of areas associated with CFAEs resulted in the termination of AF, without external cardioversion, in 95% of patients, with 91% of patients remaining free of arrhythmias at one year (18 of them after two ablation procedures).
The researchers concluded that “areas with CFAEs represent a defined electrophysiologic substrate and…ideal target sites for ablations to eliminate AF”.[10]
With the increasing use of ablation for the treatment of symptomatic recurrent AF, the accurate visualisation of areas of electrical activity that trigger and maintain AF has become
a research focus in this field. This has led to the development of software systems for the threedimensional (3D) mapping of regions of atrial electrical activity in patients with AF.
A recently-published study used 3D electroanatomical mapping software (CartoXP; Biosense Webster, CA, USA) to analyse the
spatial distribution of CFAEs in patients with paroxysmal and persistent AF. CFAEs that were detected automatically by 3D mapping matched well with the ablation sites targeted by the
operators, suggesting that automatic mapping of CFAEs can guide CFAE ablation effectively.[13]  A notable finding was that operator judgement identified a greater number of ablation sites than automatic CFAE mapping. Ablation of a proportion of these operator-identified sites had no significant effect on AF cycle length prolongation, suggesting that automatic 3D
mapping may help to avoid unnecessary ablation, and thus decrease procedural times and minimise risks of treatment-related adverse events.[13]
Since the evolution of the first 3D electroanatomical mapping systems, more sophisticated software has been developed. For
example, Biosense Webster – the manufacturer of the first commercial 3D system – has developed the CARTO RMT Electroanatomical Mapping System, which combines 3D mapping and navigation with magnetic steering technology to enable accurate visualisation and facilitate catheter manipulation. A recent addition to their portfolio, the CARTO 3 System, is designed to enable rapid electroanatomical mapping of CFAEs.

The future of CFAE ablation and 3D mapping software
The aim of CFAE ablation and electroanatomical mapping is to achieve the precise identification and controlled ablation of areas of CFAEs and, ultimately, long-term cure for patients with
persistent AF. I asked Dr Nadal for her opinion on these technologies in terms of their potential risks and benefits.
She explained that AF ablation can result in the development of atrial fibrotic scars, which may promote AF recurrence and carry a small risk of post-procedural thromboembolism.[14] In
addition, application of radiofrequency ablation to the posterior wall of the left atrium, a common area of CFAEs, is associated with a very slight risk of oesophageal injury.[15]
However, use of CFAE ablation in the treatment of AF is still in its infancy. Further research is needed to develop an appropriate definition of CFAEs and to standardise procedures, which will help to optimise the efficacy and safety of this technique. “[With CFAE ablation] you can target extensive extrapulmonary areas of fibrosis that perpetuate AF and ablate them, reducing the available area needed to perpetuate AF,” she said.
Electroanatomical mapping systems have only been used in recent years and, like CFAE ablation, remain a relatively new technology. As yet, not all institutions use these mapping
techniques and expert opinions vary as to their specificity in the identification of CFAEs. Further studies are needed regarding the application of this software in the treatment of AF. However,
these technologies offer the possibility to identify abnormalities or areas of complex anatomy that might otherwise be missed, and enable the realtime visualisation of the catheter to improve the accuracy of ablative procedures. Furthermore, electroanatomical mapping systems have already demonstrated success in AF patients in the clinic, suggesting that they may represent a significant advancement in the treatment of this complex condition.
CFAEs, then, have come to represent important therapeutic targets in the management of AF and CFAE ablation is becoming a useful tool that may be used alongside PV isolation in the treatment of patients with long-standing, persistent AF. Electroanatomical mapping systems can offer clinicians support and guidance in the accurate performance of these complex

The author would like to thank Dr Mercèdes Nadal and Dr Lluis Mont, both of the Cardiology Department (Arrhythmia Section) of the Institut d’Investigació Biomèdica August Pi i Sunyer
(IDIBAPS), University of Barcelona, Catalonia, Spain, for their guidance and support in the development of this article.

1. HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Personnel, Policy, Procedures and Follow-up. Europace 2007;9:335-79.
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