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FOCUS ON NEW MAPPING APPROACHES FOR COMPLEX ARRHYTHMIAS
Identification of Repetitive ActivationPatterns Using Novel ComputationalAnalysis of Multielectrode RecordingsDuring Atrial Fibrillation andFlutter in Humans
Emile G. Daoud, MD,a Ziad Zeidan, MD,b John D. Hummel, MD,a Raul Weiss, MD,a Mahmoud Houmsse, MD,a
Ralph Augostini, MD,a Steven J. Kalbfleisch, MDa
ABSTRACT
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OBJECTIVES The purpose of this study was to assess computational analysis of 64-electrode basket catheter (BC)
recordings of atrial fibrillation (AF) and atrial flutter using novel software, CARTOFINDER (CF).
BACKGROUND Repetitive patterns have been recorded during AF and reported to be an important mechanism of AF.
CF was used to identify rotational repetitive activation patterns (RAPs) in the right (RA) and left atrium (LA).
METHODS To assess for presence of RAPs, multiple 1-min BC maps of the RA and LA were obtained before and after
radiofrequency ablation (RFA) around the pulmonary veins in 14 patients undergoing AF ablation. Validation of the CF
algorithm was based on analysis of BC recordings of the cavotricuspid isthmus flutter.
RESULTS There were 2.9 rotational RAPs per patient (1.3 RA; 1.6 LA). No RAPs were noted in 2 patients. RFA was
delivered on top of (n ¼ 10), within 5 mm (n ¼ 5), or distant (n ¼ 10) from any RAP. Reproducibility of the BC to identify
the same RAP was 82%. Post-pulmonary vein (PV) isolation, there was a 45% reduction in RAP versus pre-RFA. CF
was validated by 4 electrophysiologists blindly reviewing 32 RA CF maps. Electrophysiologists correctly categorized
presence/absence of RAP in 122 of 128 maps (95%).
CONCLUSIONS CF is novel software incorporated into CARTO that identifies rotational RAP in the RA and LA
with 82% reproducibility. PV RFA results in 45% reduction of RAP, suggesting that RFA beyond PV isolation is
required to eliminate the bulk of RAP. Electrophysiologists who were first-time users of CF could readily identify RAPs.
T he cornerstone approach for radiofrequencyablation (RFA) of atrial fibrillation (AF) ispulmonary vein (PV) electrical isolation.
Many centers will also perform additional RFA
m the aDepartment of Medicine, Division of Cardiology, Richard M. Ross
te University, Columbus, Ohio; and the bBiosense-Webster, Inc., South D
earch grant from Biosense-Webster. Dr. Zeidan is a paid employee of Bi
visory boards for Biosense-Webster. Biosense-Webster provides financial
lowship education. Dr. Weiss has consulted for Boston Scientific, St. Jude M
other authors have reported that they have no relationships relevant to
authors attest they are in compliance with human studies committe
titutions and Food and Drug Administration guidelines, including patien
it the JACC: Clinical Electrophysiology author instructions page.
nuscript received April 18, 2016; revised manuscript received July 26, 20
(focal ablation of triggers, linear lesions); how-ever, even with extensive RFA, successful elimina-tion of AF is limited. In part, the explanation forthis reduced success rate may be that the current
Heart Hospital, Wexner Medical Center at The Ohio
iamond Bar, California. This study was funded by a
osense-Webster. Drs. Daoud and Hummel serve on
support for Ohio State University Electrophysiology
edical, BiosenseWebster, Medtronik, and Biotronik.
the contents of this paper to disclose.
es and animal welfare regulations of the authors’
t consent where appropriate. For more information,
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techniques of AF RFA do not target all AFmechanisms.
These modest outcomes have motivated asearch for mapping technology that guideablation lesions tailored to the patient’selectrical substrate. Recent studies in animalmodels and in humans have reported thepresence of focal rotors that may exist bothclose to and distant from the typical PVisolation lesion set (1–14). Ablation of right(RA) and left atria (LA) rotors has been re-ported to improve long-term freedom fromAF (15–19). One tool to create AF propagation
maps is RhythmView (Topera, San Diego, California)(19–23); however, the exact computational methodsof analyzing AF recordings is unknown and recentstudies question if these AF propagation maps areuseful to guide ablation (24). Furthermore, the find-ings of these computational maps have not beenreproduced by other endocardial techniques.
tion
SEE PAGE 217
The purpose of this study is to evaluate novelsoftware called CARTOFINDER (CF). CF is compatiblewith the CARTO electroanatomical mapping systemand is used to identify physiologic rotational repeti-tive activation patterns (RAPs). In particular, thisstudy assesses the feasibility of CF to identify RAPfrom endocardial basket-catheter (BC) recordings ofRA and LA during AF in humans, and to validate thesoftware by mapping isthmus-dependent RA flutter.
METHODS
PATIENT POPULATION. Twenty consecutive patientsundergoing RFA of AF using the CARTO electro-anatomic mapping system for clinical indications andwho consented to participate in the protocol wereenrolled (Table 1). The exclusion criteria were: 1)structural atrial disease (e.g., atrial septal patch);2) presence of a cardiac implantable electronic lead;3) mechanical mitral or tricuspid valve; 4) contrain-dication to anticoagulation; and 5) LA dimensionof $60 mm.
ELECTROPHYSIOLOGY PROCEDURE. Before theprocedure, patients underwent a transesophagealechocardiogram to exclude LA thrombus, andcomputed tomographic or magnetic resonance imageof the LA and PVs for computer 3-dimensional (3D)reconstruction of the anatomy. Antiarrhythmic drugtherapy other than amiodarone was held >5 half-livesand amiodarone was held for 4 weeks before theprocedure. Anticoagulation and antiplatelet therapywas not interrupted. General anesthesia was used in
all patients. Access was completed via the rightfemoral vein. Transseptal access was performed un-der ultrasound guidance. Intravenous heparin wasadministered to maintain an activated clotting time>300 s.
Virtual anatomy of the RA, LA, and PVs wascreated using a CARTO electroanatomic map duringspontaneous or pacing-induced AF. Although the RFAlesion set was determined by the electrophysiologist,wide area circumferential ablation around the PV ostiaand confirmation of PV entrance and exit block by a 20-pole circular mapping catheter was accomplished forevery patient. Ablation was performed with an open-irrigated tip catheter with RF energy of 35 to 45 W,and reduced energy along the posterior LA wall. AfterLA ablation, RFA of cavotricuspid isthmus RA flutterwas completed in 2 patients. Other than ablation of RAflutter, no other RA ablation lesions were delivered.
STUDY PROTOCOL. There were 2 phases of the studyprotocol. Phase I included recordings of AF anddevelopment of CF software. Phase II was the vali-dation phase with CF analysis of RA flutter (Table 2).
If the patient arrived to the electrophysiology lab-oratory in sinus rhythm, atrial pacing was performedto induce sustained AF or isthmus-dependent atrialflutter. The larger BC (Constellation, Boston Scienti-fic) (60 mm in diameter; 8 splines, 8 electrodes perspline, 6 mm apart) was used regardless of the atrialdimension. To assure maximum width of splines andendocardial contact, the BC often had to be reposi-tioned using a steerable sheath.
Phase I : Development of CF software andrecord ings of AF. Phase I protocol began with BCrecordings from the RA during AF. Before RFA, aCARTO-compatible catheter was advanced to the RAand used to create a virtual anatomical shell whichthen allowed the BC to be displayed on the CARTOscreen (Figure 1). A 1-min recording of AF was ac-quired with the BC. Five minutes later, without anychange in the BC position, a second 1-min RA AFrecording was obtained.
With completion of the RA recordings, the protocolcontinued with LA recordings. After successfultransseptal puncture and completion of the electro-anatomic LA/PV map, the BC was deployed in the LAand 2 1-min AF recordings, separated by 5 min, similarto RA recording, were obtained before RFA. Withcompletion of the pre-RFA RA and LA recordings, theBC was removed from the atria.
The electrophysiologist then proceeded with theclinically indicated RFA, starting with wide-areacircumferential ablation around the left PVs untilconfirmation of entrance and exit block. At this
TABLE 2 Summary of Phase I and Phase II Study Protocol
Phase I Protocol
Phase II Protocol
BC in RA during AF
BC in LA during AF
Complete PV isolation of left PVs
Complete PV isolation of right PVs
RFA of RA flutter
BC in RA during atrial flutter
RFA of persistent or paroxysmal AF
1-min. RA recording; Repeat 5 min. later
1-min. LA recording; Repeat 5 min. later
1-min. LA then RA BC recording during AF
1-min. LA then RA BC recording during AF
1-min. RA recording; Repeat 5 min. later
AF ¼ atrial fibrillation; BC ¼ basket catheter; LA ¼ left atrium; PV ¼ pulmonaryvein; RA ¼ right atrium; RFA ¼ radiofrequency ablation.
TABLE 1 Patient Demographics
Phase IAtrial Fibrillation
Ablation
Phase IIAtrial Fibrillation
Ablation
Number of patients 20 5
Age (yrs) 59 � 12 66 � 4
Male 13 5
Atrial fibrillation
Paroxysmal 8
Persistent 12
Duration of arrhythmia (months) 36 � 39 6 � 4
Left atrium dimensions (mm) 44 � 6 41 � 4
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juncture, the BC was redeployed in the LA for a 1-minrecording of AF. After acquiring LA, BC recordingsfollowing isolation of only the left PVs, the BC wasthen positioned in the RA to obtain a 1-minrecording. This RA recording was to assess for theimpact of LA RFA upon activation patterns in the RA.
The electrophysiologist proceeded with wide-areacircumferential ablation around the right PVs untildemonstration of entrance and exit block. If AF per-sisted or could be induced, the BC was redeployed inthe LA for 1-min recording, and then a final 1-minrecording from the RA. These recordings repre-sented the final post-RFA (right and left PV isolation)recordings of AF from the LA and RA. The BC wasremoved and further RFA was completed at thediscretion of the electrophysiologist.Development of CF. For the first 6 patients, the BC re-cordings were obtained but were analyzed offline.From these recordings, CF software was developed toidentify physiologic rotational RAPs. The definition ofa RAP is a repetitive activation pattern present for atleast 3 consecutive cycles during a 1-min AFrecording, identified by visual interpretation of theBC activation pattern.
CF is based on assessment of local activation timeof atrial signals during AF. The algorithm entails(Figure 2): 1) create CARTO matrix; 2) record AF withBC and filter out far field ventricular signals; 3) foreach BC electrode, the position of the 2 closestelectrodes is known from the CARTO matrix; 4) foreach unipolar electrode of the BC catheter, 2 bipolaratrial signals are created by using the nearest 2electrodes, thus 120 bipoles recordings are obtained;5) from these 2 bipoles, created for each electrode,the Bipolar Electrogram Window is established,based on measurement of the earliest onset tolatest offset of the 2 bipole electrograms; and 6) thebipolar electrogram window establishes the windowto record the unipolar atrial signal from the specificelectrode. The next step is to perform a waveletanalysis of unipolar signals recorded from the
bipolar electrogram window. This analysis uses aproprietary algorithm to annotate only high-qualityunipolar signals.
The final step is generation of dynamic 3D propa-gation maps (Figure 3). The local activation time ofthe atrial unipolar signals are assessed by comparingthe activation times during a window of interest. Thewindow of interest duration is 90% of the atrial uni-polar cycle length histogram. As the window of in-terest moves through the unipolar atrial signals, thelocal activation time is annotated in color, labeling
FIGURE 1 Image of BC in RA and LA
(A,B) Fluoroscopic images of the basket catheter (BC) in the right atrium (RA) and the corresponding display of the BC on the 3-dimensional
(3D) CARTO RA anatomic map. (C) The BC on the 3D CARTO left atrium (LA) anatomic map. (D) The repetitive activation pattern (RAP) recording
from the LA superimposed upon the BC and the CARTO map.
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the leading edge of activation with red color so tocreate a propagation map that is displayed on theCARTO electroanatomic map. These activation mapsare then reviewed by the electrophysiologist toidentify RAP. Gray color on the CF map representsareas of no atrial signals.CF Recordings of AF. With development of CF soft-ware, the subsequent 14 study patients were enrolled
and the BC maps were analyzed offline using CFsoftware to generate RAP maps. The CF maps werereviewed by 4 investigators to visually identify eachRAP. By displaying the CF maps upon the virtualanatomic shell, the distribution of the RAP relativeto the final ablation lesion set could be determined.The RFA lesion set relative to the CF RAP map wascharacterized as on top of, within 5 mm, or distant
FIGURE 2 Filtering Ventricular Far-Field Signal and Annotation of Local Activation Times
(Top to bottom) The first step of CF algorithm is subtraction of the averaged ventricular far-field signal (VFF); then, calculation of 2 bipolar
signals for each unipolar BC electrode; followed by calculation of the bipolar electrogram window, which is the earliest onset to the latest
offset of the 2 bipole electrograms. (Bottom) Using the bipolar electrogram window, the unipolar atrial signal is recorded from the specific BC
electrode. (Images courtesy of Richard Houben, PhD.) BS ¼ baseline; ECG ¼ electrocardiogram; IC ¼ intra-cardiac; other abbreviations as in
Figure 1.
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from any RAP. The results of these 14 patients arepresented.Phase I I : CF record ings of atr ia l flutter andval idat ion . To validate the CF recordings during AF,CF software was used to analyze an arrhythmia inwhich a RAP is well defined: that is, BC recordings ofisthmus-dependent RA flutter were used. Five pa-tients were referred for ablation of cavotricuspidisthmus-dependent atrial flutter, confirmed by acti-vation pattern and response to entrainment.
Before RFA, a CARTO virtual anatomical RA shellwas created, and the BC was then deployed. A 1-minatrial flutter recording was acquired from the BCand was repeated 5 min later. The BC was thenremoved and the clinically indicated ablation wascompleted. The atrial flutter BC recordings wereanalyzed by CF.
To validate CF, RA CF maps were randomlyreviewed by 4 electrophysiologists blinded to thearrhythmia and to the methodology of the CF soft-ware. The reviewers were only provided the CARTOelectroanatomic maps with the superimposed CFactivation maps and were asked to determine if an
RAP was present based on visual assessment.The agreement between pairs of physicians wascalculated as the observed agreement, which is thepercentage of all maps for which the reviewers agreeto the presence/absence of an RAP. Kappa statisticsrepresents how different the observed inter-observeragreement is from the expected agreement by chance.The results are presented as Kappa coefficientwhere the value of 1 means perfect agreement and0 represents if agreement is by chance.
RESULTS
RAPs IDENTIFIED WITH CF. CF recordings werecompleted in 14 patients without complications(Figure 4, Online Video 1). Based upon visual inter-pretation of the CF maps, no RAPs were noted in 2patients and 39 RAPs were identified in 12 patients.There were 17 (44%) RA RAPs and 22 (56%) LA RAPswith 2.8 RAPs per patient (mean of 1.3 RA RAPs and 1.6LA RAPs). The RA RAPs were located on the septum(n¼ 9), anterolateral (n¼ 5), and posterior (n¼ 3) walls.The LA RAPs were located on the anterior (n ¼ 8), roof
Yellow dots annotate the local activation times on the atrial unipolar signals. The colored window of interest moves through the atrial unipolar
electrograms (left to right) and as the unipolar signal enters andmoves through the window of interest, that region of the CARTOmap (on left of
image) is annotated by the particular color (color range red to blue; note this varies from the conventional CARTO color range “redmeets purple”).
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(n¼ 7), and posterior (n¼ 7) walls. Videos of LA and RACF activation maps during AF showing RAP are avail-able online (Online Video 2). Characteristics of theRAPs are summarized in Table 3. All RAPs were rota-tional lasting for at least 3 cycles. The center of a RAPmoves only slightly within amaximum radius of 5 mm.
When comparing the first BC recording to the sec-ond recording obtained 5 min later in the RA and LAbefore RFA, the correlation to identify the same RAPwas 14 of 17 in RA and 18 of 22 in LA (total: 32 of 39,82%; no difference between RA and LA).
Following isolation of only the left PVs, a BCrecording was obtained of the RA to assess if LAablation altered distant RAP. Of 14 patients, a map ofthe RA was not repeated after left PV isolation in 5patients since the rhythm either converted to sinus orwas atrial flutter. In the remaining 9 patients, 10 of 13(77%) RA RAPs identified at baseline remained un-changed after left PV isolation.
When comparing the CF maps to the final CARTOablation lesion set, RFA was delivered on top of(n ¼ 10), within 5 mm (n ¼ 4), or distant (n ¼ 8) fromany LA RAP (Figure 5). After PV isolation, BC re-cordings demonstrated a 45% reduction in RAP incomparison to prior ablation; and 11 of 16 patientsconverted to sinus (n ¼ 7) or transitioned tononisthmus-dependent atrial flutter (n ¼ 4).
ISTHMUS-DEPENDENT FLUTTER MAPS AND VALIDATION
PHASE. CF maps during RA isthmus-dependentmacro-reentrant flutter identified 1 RA RAP ineach patient rotating around the tricuspid valvewhen viewed in the left anterior oblique position(Figure 6, Online Video 3). The reproducibility ofidentifying the single RAP was 100%.
The CF algorithm was validated by randomizedreview of 32 RA CF maps by 4 electrophysiologists.The inter-observer variability for simple agreementbetween pairs of the 4 observers of the CF RAPs is0.91, and the average Kappa between pairs ofobserver is 0.71. The 32 RA CF maps included 23 of RAisthmus-dependent atrial flutter, 4 of RA during AFwith RAP present, and 5 of RA during AF but no RAPidentified. The electrophysiologist correctly catego-rized the presence/absence of an RAP in 122 of 128(95%) CF maps. Online Video 3 displays RA isthmus-dependent flutter.
DISCUSSION
MAIN FINDINGS. CF is novel software incorporatedinto a conventional 3D mapping system, CARTO,allowing identification of RAP relative to the virtualanatomical shell, as confirmed by the validationphase in patients with atrial flutter. This first in-man
FIGURE 4 Representation of RAP Recorded From LA During AF
Example of a counterclockwise RAP recorded during AF in the anterior wall of the LA. The CF analysis is displayed on top of the CARTO 3D
anatomic map (Online Videos 1 and 2). The leading edge of the local activation is represented by region of red and depicts a RAP (white circular
arrow around the asterisk). 3D ¼ 3-dimensional; AF ¼ atrial fibrillation; CF ¼ CARTOFINDER; other abbreviations as in Figure 1.
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evaluation of CF revealed several findings: 1) the CFsoftware reliably and reproducibly creates accuratemaps of macroreentrant flutter; 2) physiologic rota-tional RAPs were identified in the majority of patients
TABLE 3 Characteristics of Recorded Repetitive Activation
undergoing RFA AF (86%); 3) the reproducibility ofthe presence of RAP during AF, using CF recordingsseparated by 5 min, was approximately 80%; 4) PVisolation resulted in a 45% reduction of RAP; 5)ablation in 1 atrium can seemingly impact RAP in theother (i.e., ablation in LA reduced RAPs recorded inthe RA by 23%); and 6) identification of RAP on CFmaps is readily achieved by electrophysiologists.
MECHANISMS OF AF. There are 2 prevailing proposedmechanisms of AF. The first is based on seminal workby Moe and Allessie that attributes AF to multipledisorganized meandering wavelets with numerousintramural waves and wave breaks with epicardialbreakthrough (25–27). These findings were supportedby detailed human mapping revealing the spatio-temporal characteristics of AF (3,7). In this model, the
FIGURE 5 CF Maps Displayed Upon the CARTO 3D Anatomic Map After Completion of Ablation
The red tags denote the ablation lesion set. The RAP is denoted by the white circular arrow around the asterisk. On the left (A), the ablation
lesion was delivered on top of the RAP; and on the right (B), the ablation lesion was distant from the RAP. Abbreviations as in Figures 1 and 3.
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wavelets are randomly distributed in the RA and LAand there are no focal AF drivers. The second theoryis that AF is due to localized sources with fibrillatoryconduction, as supported by studies in man and in AFoptical dye maps (1,4–6,8–14). These localized sourcesoften have a pattern of activation of a spiral wave,termed a rotor, and are believed to sustain AF. Iden-tification and targeting rotors for ablation has becomethe basis for moving away from anatomical-basedablation to a patient-specific ablation lesion setbased upon mapping AF activation pattern andidentifying AF rotors (17–21). If AF is attributable tomultiple disorganized meandering wavelets, a spe-cific ablation lesion set based upon the substrate isimprobable and likely unwarranted; however, iflocalized sources/rotors are essential, then a tech-nique for correlating AF activation maps with the 3Dgeometry of the RA and LA becomes essential.
PRIOR STUDIES. Narayan et al. (17) and others havereported upon a technique of computational analysisof BC recordings of LA and RA during AF to generateactivation maps (17–21). This technique is called focalimpulse and rotor modulation (FIRM). Similar to thecurrent study, FIRM mapping demonstrated 1.9 � 1.1sources per patient, with the majority of the sourceslocated in the LA (67%), and that the AF sources werecoincidentally ablated with PV isolation in 45% ofpatients. Outcomes following AF ablation guided by
FIRM maps have been encouraging, but recentreports challenge earlier results (24).
A major difference between FIRM and CF maps isthe technique of mapping rotational activity. FIRM isbased upon regional action potential duration resti-tution and regional conduction restitution defined byconduction time to each basket electrode (22). CFmaps are generated by local endocardial activationevents recorded from each basket electrode comparedto surrounding electrodes.
STUDY LIMITATIONS. The major limitation of thisstudy are that it still remains unclear if identifica-tion of RAP equates to RAP being a mechanism ofsustaining AF, and if ablation of RAP will enhanceoutcomes of AF ablation. RAP may be a coincidentalphenomenon of meandering activation of the atriaby wavelets. Clinical trials are ongoing to investi-gate the value of targeting RAP for RFA. Nonethe-less, the validation phase of this study confirmsthat the CF software accurately identifies RAP andthat these RAPs are readily identified by blindedreviewers.
Another limitation of this study is similar to allmapping systems based on basket technology;despite special attention and effort, basket electrodeswere not consistently deployed evenly and with sta-ble contact to allow mapping of the entire atria, valveannuli, and within PVs.
FIGURE 6 RAP Recorded From RA During Cavotricuspid Isthmus-Dependent Atrial Flutter
This is a left anterior oblique CARTO 3D anatomic image with the tricuspid valve cut away displaying a counter-clockwise rotating RAP (white circular arrow around
asterisk) of cavotricuspid isthmus-dependent RA flutter (Online Video 3). Abbreviations as in Figures 1 and 3.
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One other limitation is that, when comparing thefirst and second BC recordings, the definition ofpresence of the “same” RAP was based upon visualinterpretation of similar activation pattern, located inthe same region of the atria. There was no method-ology used to define that the RAP was exactly un-changed from one recording to another. Furthermore,it was not feasible to simultaneously map RA and LAactivation of the endocardium and epicardium as wellas the coronary sinus.
CONCLUSIONS
For more than a decade, enhancements in AFablation have focused upon accuracy of anatomical
maps and permanency of ablation lesions; however,recently, attention has been directed to identifypatient-specific features. Rather than empiricanatomic-guided ablation, lesion sets are beinggenerated through use of scar distribution and atrialvoltage maps, noninvasive electrocardiographic im-aging, and identification of rotational activationwith FIRM maps. However, the likelihood for anysingle technique to be applicable to all patientsmay be low. The difficulty of finding a reliableAF ablation methodology may reflect that there iscoexistence of variety of mechanisms contributingto AF and to varied degrees for an individual pa-tient. This study is a first step to demonstrating thevalue of CF software as another potential mapping
rent approaches to ablation of atrial fibrillation focus
upon anatomic goals of pulmonary vein isolation.
Based upon this study, as well as others, subsequent
investigations should evaluate the incremental value
of modifying electrically identified substrate.
TRANSLATIONAL OUTLOOK: Multicenter ran-
domized trials are required to evaluate the reliability
of mapping technologies to identify patient-specific
AF electrical properties and to assess if ablation of
these regions results in greater freedom of AF.
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tool that offers easily interpretable AF activationmaps. CF maps of AF activation coupled with theelectroanatomical and voltage information providedby CARTO may offer a multimechanistic approach topatient-specific AF ablation. Whether CF mapsadded to CARTO data will enhance AF ablationoutcomes remains to be determined by ongoingclinical trials.
ADDRESS FOR CORRESPONDENCE: Dr. Emile G.Daoud, Department of Medicine, Division of Cardiol-ogy, Richard M. Ross Heart Hospital, Wexner MedicalCenter at The Ohio State University, 473 W. 12thAvenue, DHLRI, Suite 200, Columbus, Ohio 43210-1252. E-mail: [email protected].
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