DOI: 10.1161/CIRCEP.115.002721

Quantitative Analysis of Localized Sources Identified by Focal Impulse and Roter Modulation Mapping in Atrial Fibrillation

Running title: Benharash and Buch et al.; FIRM ablation results

Peyman Benharash, MD1*; Eric Buch, MD1*; Paul Frank, MD1; Michael Share, MD1; Roderick Tung, MD1; Kalyanam Shivkumar, MD, PhD1; Ravi Mandapati, MD1,2

1

UCLA Cardiac Arrhythmia Center, UCLA Health System, David Geffen School of Medicine at U UCLA, CLA LA,, Lo LA Los os Angeles, CA; 2Loma Linda Uni University iveersity Medicall Ce C Center, nterr, Loma Linda, CA *Joint *J Joinnt first firstt authors auuthhor hors

Correspondence: Correspo pond po nden nd ence en ce:: ce Eric Eriic Buch Er Buch, h, MD UCLA Cardiac Arrhythmia Center David Geffen School of Medicine at UCLA 100 UCLA Medical Plaza, Suite 660 Los Angeles CA 90095-1679 Tel: 310 206 2235 Fax: 310 8252092 E-mail: [email protected]

Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs, [22] Ablation/ICD/surgery, [132] Arrhythmias - basic studies

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DOI: 10.1161/CIRCEP.115.002721

Abstract: Background - New approaches to ablation of atrial fibrillation (AF) include focal impulse and rotor modulation (FIRM) mapping, and initial results reported with this technique have been favorable. We sought to independently evaluate the approach by analyzing quantitative characteristics of atrial electrograms (AEGMs) used to identify rotors, and describe acute procedural outcomes of FIRM-guided ablation. Methods and Results - All FIRM-guided ablation procedures (n=24, 50% paroxysmal) at UCLA Medical Center were included for analysis. During AF, unipolar AEGMs collected from a 64pole basket catheter were used to construct phase maps and identify putative AF sources. These sites were targeted for ablation, in conjunction with pulmonary vein isolation (PVI) in most patients (n=19, 79%). All patients had rotors identified (mean 2.3 ± 0.9 per patient, 72% in LA). Prespecified acute procedural endpoint was achieved in 12/24 (50%) patients: AF F ttermination ermi er mina mi nati na tion ti on (n=1), electrodes n=1), organization (n=3), or >10% slowing of AF cycle length (n=8). Basket elect ctro ct rode ro dees we were re within mean with hin 1cm 1cm of of 54% 544% of LA surface area, and a me ean ooff 31 electrodes perr pa patient showed interpretable Offline analysis distant sites nteerpretable AEGMs. AEG EGMs Mss. Of Offl flin fl i e an in anal alys al ysis ys is rrevealed e ea ev eale led noo ddifferences le iffe fere fe renc re nces nc e bbetween etwe ween we en n rrotor o or aand ot nd di dist s an antt si site tess in te i dominant Shannon entropy. Electroanatomic mapping showed dom do minant frequency frequeency orr S hanno non entrop no py.. Ele ecttroan natom mic m apping ng showe wed no rotational we rotattioona onal activation FIRM-identified rotor sites acti tiva ti vati va tion ti on at F IRM IR M-i -ide dent de ntif nt ifiedd ro if roto torr si to site es in 23/24 23/ 3/24 24 patients pat atie ient ie ntss (96%). nt (96% (9 6%). 6% Conclusions AEGM characteristics Conclusi sion si onss - FIRM-identified on FIRM FI RM--ide RM -ide dent ntif nt ifie if iedd rotor ie roto ro t r sites to site si tess did te did not noot exhibit exhi ex hibi hi bitt quantitative bi quan qu anti an tita ti tati ta tive ti ve A EGM EG M ch char arac ar acte ac teri te rist ri stic st i s expected rotors, differ expe ex pect pe cted ct ed ffrom rom ro m ro roto tors to rs,, an rs andd di didd no nott di diff ffer ff er qquantitatively uant ua ntit nt itat it ativ at ivel iv elyy fr el from om ssurrounding urro ur roun ro undi un ding di ng ttissue. issu is sue. su e. Catheter Cath Ca thet th eter et er aablation blat bl atio at ionn io of these sites, in conjunction with PVI, resulted in AF termination or organization in a minority of patients (4/24, 17%). Further validation of this approach is necessary.

Key words: atrial fibrillation, catheter ablation, rotor

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DOI: 10.1161/CIRCEP.115.002721

Background Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in adults, and is associated with thromboembolic complications, myocardial and neuronal remodeling and increased mortality.1 Surgical and percutaneous treatments involve ablative therapy targeted at isolating or eliminating putative arrhythmia triggers and substrate sustaining AF. Although Haissaguerre and colleagues found pulmonary vein triggers in the majority of paroxysmal AF patients,2 the mechanisms underlying AF maintenance remain elusive, leading to suboptimal outcomes for catheter ablation. Ablation results are particularly disappointing for longstanding persistent AF, in which complex substrate and patient-specific sustaining mechanisms have been reported. eported.3, 4 This has led to a wide range of procedural approaches to persistent A AF F ab abla ablation, laati tion on,, with on most ooperators p rato pe ors tar targeting arge g ting atrial substrate in additionn to t pulmonary vein is isolation sol o ation (PVI) and abla ab ablation ation of other otthe herr triggers. trig tr gge gers rs..5 rs More re rece recently, enttly, ph physio physiologic olo logi g c ma mapp mapping pppin ng ooff A AF F ha has a be bee been en uutilized tiilizeed to id identify den ntify fy areas areas of of the th he atrium atriium m that hat mayy be be responsible resp spon sp o sibl blee fo bl fforr ma maintaining ain intainingg AF,, in i an an attempt attemp at pt to t identify identiffy patient-specific p tien pa nt-sppec ecific drivers to -9 design desi de s gn ttailored si a lo ai ore redd ab abla ablation lati la tion ti on sstrategies. trat tr ateg at egie eg iees.66-9 One O ne ssuch uchh me uc meth method t od w th with itth pr prom promising omis om issin ingg results resu re sult su ltts iss focal foc ocal al iimpulse mpul mp u se ul

and rotor modulation (FIRM). This technique utilizes panoramic sampling of the atria and computational spatiotemporal mapping in order to identify putative regions of recurrent organized rotational activity, or rotors, as well as focal drivers.10 Narayan and others have reported the presence of stable rotors in humans and that ablation of FIRM-identified localized sources results in high rates of acute termination and long-term freedom from recurrent AF.10-12 Based on prior mechanistic studies, rotor sites are expected to exhibit greater electrical periodicity, unique spectral characteristics such as higher dominant frequency6, and higher Shannon entropy9, distinguishing them from other atrial sites13-15. Quantitative analysis of

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DOI: 10.1161/CIRCEP.115.002721

electrograms (EGMs) recorded at rotor sites identified by FIRM mapping has not yet been systematically validated and reported. Accordingly, we hypothesized that FIRM-identified localized sources would show distinctive characteristics in frequency domain and entropy analysis, and evidence of rotational activity on electroanatomic mapping. Additionally, we report the rates of termination, organization, or slowing of AF cycle length associated with rotordirected ablation, and compare patients with acute procedural success to those with acute failure.

Methods Patient Population The institutional review board at the University of California, Los Angeles approv approved oved ov ed retrospective etrospective review of this data. Consecutive patients undergoing FIRM-guided ablation abl blation for paroxysmal January paarooxysmal oorr persistent AF at UCLA Medical Center Ceentter between Ja anu n ary 2012 and July 2013 were included FIRM-guided (FIRM-only) nclluded in the study. study. Patients Patientts includedd underwent undeerw wentt oonly nlyy FI FIRM RM-guuidded ablation RM ab blaatiion (FIRM RM-oonlly) oorr RM FIRM-guided (FIRM+PVI). FIRMM gu guid ided ablation id ablat atio tio i n foll ffollowed oll l owed ed bby y PVII (F (FIR IRM+ IR M+PV M+ PVI) PV I). Other I) Othher Ot her publ ppublications u lic icaatio ations ns included include dedd data de dataa ffrom rom ro m 1 oof these patients hese pa ati tien entts en ts11 aand nd 111 1 of tthese hese he se ppatients. atiient at ntss.122 nt Electrophysiology Study Antiarrhythmic medications were discontinued in paroxysmal patients for 5 half-lives (60 days for amiodarone), and were left to operator discretion for persistent patients. All patients were anticoagulated for at least 30 days prior to ablation; warfarin was uninterrupted with target INR 2-3 at ablation, novel oral anticoagulants were held for 24 hours and restarted the next day, with intravenous heparin overnight. All patients had transesophageal echocardiography to rule out left atrial (LA) thrombus immediately before the procedure. Catheters were advanced from the femoral and jugular veins to the right atrium (RA), coronary sinus, and LA via transseptal puncture. A 64-pole basket catheter (Constellation, Boston Scientific, Natick, MA) was 4 Downloaded from http://circep.ahajournals.org/ at University of Manitoba Libraries on June 10, 2015

DOI: 10.1161/CIRCEP.115.002721

advanced through an 8.5F SL0 sheath (Daig Medical, Minnetonka, MN) to map electrical activation in both atria. The basket catheter was manipulated to optimize electrode contact with the atrial surface and maximize coverage of the entire chamber. One of the electrodes from a quadripolar catheter situated in the superior vena cava was used as a unipolar reference. Three-dimensional electroanatomic mapping was performed using the Ensite Velocity system (NavX, St. Jude Medical, Minneapolis, MN). Intravenous heparin was infused prior to deployment of the basket catheter with goal activated clotting time >300 seconds. Figure 1 shows basket catheters in the LA via transseptal puncture (Fig. 1A-C) and a sample of the 64 unipolar electrograms (EGMs) recorded (Fig. 1D). Unipolar EGMs were bandpass filtered between 0.05 Hz andd 500 Hz and recorded at 1 kHz sampling frequency (Prucka, a,, GE GE Healthcare, Heal He alth al thcare th Waukesha, Waukes e ha,, WI). W ).. WI presenting atrial pacing, beginning For ppatients a ie at ient nts pr nt pres esen es enti en ting ti ngg iinn sinus sinu si nuss rhythm, nu rhytthm rh hm, AF F was wass induced ind nduc uced uc d bby y at atri riial bu bburst rsst pa paci cing ci n , be ng begi ginn gi nnin nn ing in reducing 180 mss unt until att 500 0 ms cycle cycl c e llength enngth h aand n red nd educ ed u ingg to t 18 80 m til AF F was wass induced. induuceed. Iff AF AF was wa nott sustained suusttaiinedd for fo minutes, repeated necessary at least 5 mi m nutees, isoproterenol isoopr prot o erenol ol was infused d aand ndd pacing pac a ingg wa was repe p ated e as nece ed cessar ce aryy to induce ar sustained ust stai a ne ai nedd AF. AF. FIRM Mapping of AF Sources The rationale, algorithms, and methods of identifying AF sources using FIRM mapping have been described elsewhere.10, 16 Briefly, basket catheter data is exported to a proprietary mapping system (RhythmViewTM, Topera Medical, Palo Alto, CA), which filters out QRS complexes and T waves, and analyzes the unipolar atrial EGMs, taking into account rate-dependent repolarization and conduction slowing in order to determine physiologically plausible activation paths. The resulting computational phase maps depict putative propagation of electrical activity during AF, displayed as a grayscale animation. Intraoperatively, two operators examined the

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DOI: 10.1161/CIRCEP.115.002721

movies to qualitatively identify sites of recurrent clockwise or counterclockwise rotational activity, or focal sources that initiated centrifugal atrial activation. Sources were targeted if both operators agreed on the location of a rotor or focal source. Rotor centers were localized on the basket catheter as either adjacent to a single electrode, or a 1X1 electrode area bounded by adjacent electrodes on adjacent splines. Technical representatives from Topera Medical were present for all cases, and an experienced FIRM operator was on site for 18/24 (75%) cases, acting as primary operator in 11/24 (46%) cases. Catheter Ablation Procedure FIRM sources in both the right and left atria were targeted using a 3.5mm-tip radiofrequency (RF) RF) irrigated ablation catheter (Thermocool, Biosense Webster, Diamond Bar, CA CA)) at 225-35 5-35 535 Watts, s,, maximum maxim mum m temperature 42°C. The ablation catheter cat a heter was directed tto o tissue adjacent to the basket center identified rotor region, using baskket electrode ba electroodee near nea e r the the ce cent n er ooff th nt thee id iden e ti en tifi fied fi e ro oto or re egi gion on,, us on sin ingg fluoroscopy fluo fl uooro rosc s oppy and and electroanatomic applied until el lec ectr t oanatomi tr m c mapping. mapppin ng. g Energy Ene nerg ne r y wa rg was ap pplieed unt til lo lloss ss of of local loccal EGM EG aand ndd ddrop ropp in iimpedance ro mpeedaancee aatt mp the seconds RF). was targeting region within he site (20-40 (20 20-40 se 20 seco c ndds of o RF) ). A lesion set w ass ccreated, reat re a ed,, tar a ge g tingg the h reg he gionn with thin a 1-2 cm th radius rotor coordinate, until adi d us ooff th tthee ro roto torr co to coor ordi or d na di nate te,, un te unti t l AF ttermination/organization ti ermi er mina nati na t on ti on/o /org /o rgan rg aniz an izat atio at io on or electrogram ele lect ctro ct rogr ro gram gr am rreduction educ ed ucti uc tion ti on ooff th tthee rotor region was observed (5-10 minutes of RF). When AF organized into a regular atrial flutter or tachycardia, this was mapped and ablated with conventional approaches. When AF terminated, reinduction was attempted with the same pacing protocol and a new FIRM map was created. When AF did not terminate, the next FIRM-identified rotor site was targeted for ablation. If the patient remained in AF after all FIRM sources were treated, direct-current cardioversion was performed. At that point, the procedure was terminated (FIRM-only group), or circumferential antral pulmonary vein isolation was performed (FIRM+PVI) with a circular mapping catheter (Optima, St Jude Medical, St. Paul, MN) to verify LA-PV conduction block.

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No LA roof or mitral isthmus lines were created. Esophageal temperature was monitored and energy delivery was interrupted for any temperature rise of >1°C. Offline Data Analysis A: Multipolar basket catheter assessment Atrial surface area coverage with the basket catheter was assessed by first calculating the endocardial LA surface area by segmentation of the electroanatomic three-dimensional shell (Fig. 2). We then determined the proportion of LA surface area within 10 mm of any basket catheter electrode, with the catheter deployed at the position leading to the first FIRM-identified LA source targeted for ablation. B: Construction of activation maps catheter were To assess asssess adequacy adeq e uaacy c of electrical signals, basket cat the h ter unipolar EGMss we w re studied to determine used channels with dete de ermine iff a vvoltage olta ol t ge tthreshold hres hr esho es h ld could ho cou ould ld d be be us sed to eexclude xccludde ch chan a neels w an i h on it only nnoise oise oi se or or indecipherable signals. Selection threshold nde deci c pherable le sig ignnalss. S ig elecctiion off a th hreeshoold old value vaalu ue too allow allow ow automatic auutomaticc annotation annnottat a ionn with withh NavX NavX vX electrophysiologists was attempted. attemp mpted. Two mp Two w experienced exp xperienced ed electroph p ys ysio i lo logi gist gi s s independently st indeepe pendentlyy examined examin ned e each eac a h EGM and annotated adequate EGM was anno an nota no tate ta tedd ti te ttiming ming mi ng of of local lo oca call atrial atri at rial a activation; al act ctiv iv vat atio io on; an an ad adeq equa eq uate ua te E GM w as ddefined e in ef ined ed aass one one in which whi hich ch local loc ocal a al activation time could be manually annotated at any gain setting. This was done at the peak deflection of each atrial EGM in segments without a QRS complex, to minimize distortion by ventricular activation. Electroanatomic mapping was used to create propagation and isochronal maps for 20 consecutive sequences, each 200 ms. Data were analyzed for rotational activity (defined as in other studies as 2 or more complete rotations of 360 degrees) or focal sources with centrifugal atrial activation. C: Frequency domain analysis and entropy For quantitative analysis of atrial electrical activity, far-field ventricular activity was subtracted

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DOI: 10.1161/CIRCEP.115.002721

from the raw unipolar signals by filtering to remove baseline drift and electrical noise, locating the peak of each R wave, and selecting a surrounding segment that included the QRS complex and T wave (Fig. 3). An aggregated QRS-T complex was subtracted from each segment, leaving atrial activity as the remainder signal for each of the 64 channels. The dominant frequency and Shannon entropy were then calculated from the remainder signal. Frequency domain and entropy analyses were performed using custom-made programs in LabVIEW 2013 software (National Instruments, Austin, TX). Briefly, a Fourier transform function was employed to decompose each unipolar electrocardiogram into its component sinusoidal functions. The dominant frequency was defined as the frequency with the largest amplitude from 1-20 Hz, as calculated by the Fourier transform. Shannon entropyy was w s calculated wa calc ca lcul lc ulatted ul to measure o mea asure the h ddegree eg gree of disorganization for each wa waveform. This was ccalculated alculated by the formula al Sh ShEn hEn

m

¦ P ( xn ) lo log P ( xn ) n 0

wheree P(x P(xn) is the the probability pro roba babi ba bility of bi of a given givenn ou outc outcome, tcoome, tc ome aand nd m iiss th thee nu number umb mber err ooff possib ppossible o ib ible le outco outcomes. come co mes. me s Appliedd to this this analysis, anal an alys al ysis ys is, ea is each ch ddata ataa po at poin point intt re in repr represents pres pr esen ents en ts aan n in inst instantaneous stan st anta an tane ta neou ne ouss vo ou volt voltage lttag agee me meas measurement. asur as urem ur emen em en nt. For each channel, the range of voltage measurements was divided into 100 bins (m=100), and the proportion of all voltage measurements within each bin was given by P(xn). Acute Ablation Endpoints Outcomes were assessed during the ablation procedure and in the immediate post-procedural period. For patients who began the procedure in sinus rhythm, the primary acute efficacy endpoint was defined as termination or organization of AF, or slowing of AF cycle length by >10% during RF application, and non-inducibility after ablation. For patients who began the procedure in AF, acute efficacy was defined as termination of AF at any point during the procedure or slowing of AF cycle length by >10% from beginning to end of the procedure

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(including PVI). Safety endpoint included adverse events within 30 days of the index procedure. AF cycle length was determined for each patient at the start of the procedure, after each rotor ablation, and at the end of the procedure. A total of 30 cycle lengths were measured in the coronary sinus catheter and averaged for each cycle length measurement. Statistical Analysis Categorical variables were compared using the chi-square or Fisher’s exact tests, expressed as numbers and percentages. Continuous data are reported as mean r standard deviation, or median with 25%-75% percentile range for small sample sizes. Patients were grouped based on acute procedural success and compared to those without acute success. Unpaired t-test was used to rotor estimate differences in continuous variables between groups. When comparing ro otor o ssites or ittes tto o nonrotor sites, account otor si site tes, te s, a linear l neear mixed effects repeated measures li es model was used to ac acco c unt for within subject among multiple from Z-test ubjject correlation correl ellattio ionn am mon ongg mult m ult ltip iple ip le oobservations bser bs erva rvaati tion ons n fr rom m tthe he ssame ame pati am ppatient. atiien ent. t. We W uused sedd th se thee Z-te test st ooff proportions ablation, FIRM FIRM+PVI, pr rop opor o tions too compare co omparre subgroups subgr grou gr oups based ou bas a ed on type typpe of ty of AF, AF pprior rio or abla atiion, aand ndd FIR F IRM vvss F IRM RM+P RM PV I acute 1 rotation) on electroanatomic mapping was not observed at FIRMidentified rotor sites; and 4) Ablation of rotor sites, even when accompanied by PVI, did not result in AF termination in the majority (20/24, 83%) of patients. 12 Downloaded from http://circep.ahajournals.org/ at University of Manitoba Libraries on June 10, 2015

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To the best of our knowledge, this is the first report of systematic quantitative study of electrograms recorded at putative rotor sites identified by FIRM mapping. Feasibility of Panoramic Atrial Mapping with the Basket Catheter We found the Constellation basket catheter left large areas of the atrial surface unsampled, usually due to anatomic variation leading to poor contact or clustering of splines. Even within regions that had adequate physical sampling (55% of LA surface area), the majority of atrial EGMs were of such poor quality that activation time could not be manually identified by two experienced electrophysiologists, and thus were indistinguishable from noise. The resulting activation maps were of such low resolution that it was difficult to precisely identify the site of any localized sources for ablation. Newer catheter designs might improve atrial ccoverage ove v raage aand nd signal Medical, Alternatively, ignal quality quality y (e.g. (e..g. g FIRMap catheter, Topera Medic cal a , Menlo Park, CA). ). A lternatively, other approaches mapping mapping might appr ap prroaches ssuch uchh as uc a bo body dy ssurface u faace m ur a pi ap ping n oorr hi ng hhigh-resolution gh--reesollut utio ionn epicardial io e ic ep icarrdi dial all m a pi ap ping ng m ightt pprovide ig rovi ro vide vi de better higher ratio. beett tteer er coverage coverag ag ge an and hi igh her signal-to-noise siign ignal-to o-n -nooisse ra atio io o. Quantitative Characteristics Quantitaati t ve C h ract ha cter ct eristics ooff FIRM-Identified er FIRM-Iden entiifi en fied ed Rotorr Sites In study, EGMs recorded identified rotors quantitatively n tthis hiss st hi stud udy, ud y, E GMss re GM reco cord co rdded ffrom rom ro m si ssites tess id te den enti t fi ti fied ed aass ro roto tors to rs ddid id d nnot ot ddiffer iffe if ferr qu fe quan anti an t ta ti tati t ve ti vely ly ffrom rom ro m other atrial sites in dominant frequency or Shannon entropy. In animal models, rotors characterized by a series of stable high-frequency EGMs around the repetitive circular path have been described.15 We did not see regular, monomorphic electrical activity in any of the FIRMidentified rotor areas. Consistent with previous reports on human AF failing to demonstrate stable reentrant rotors,17, 18 we could not find evidence of sustained rotational activity on isochronal activation maps. Narayan and colleagues have previously suggested19 that expectation of regular signals near a rotor core or ‘anti-phase’ signals at opposite equatorial points of a circular trajectory is a gross oversimplification of AF dynamics, in which rotors precess to

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DOI: 10.1161/CIRCEP.115.002721

produce variable EGMs.20 However, even if this is true, regular monomorphic EGMs should be observed close to the rotor core. In summary, rotor sites were not mathematically distinct from background noise during AF using multiple established analytic methods. Nor did FIRM-identified rotor sites show quantitative characteristics that would allow for prediction of ablation success. Although the possibility that the proprietary FIRM algorithm processes electrophysiologic information in a unique method beyond traditional mapping techniques cannot be excluded, objective corroborating analytical methods could not confirm the presence and location of these purportedly stable localized sources. Acute Results of Catheter Ablation at Rotor Sites Catheter Cathetter ablation ablat a ionn of all FIRM-identified rotor sitess di ddidd not lead to AF termination ter ermi m nation or organization inn 83% 83% of procedures, proc o ed oc edur u ess, an andd oonly nlly hhalf alff could al co oul uldd be considered conssiddereed su succ successful ccessf cc sful sf ull with w th the wi th less leess rigorous rig igor o ou ouss acute acut ac utee ut endpoint en ndppoi o nt of AF A cycle cy llength enngth slowing. slo lowingg. These Theese results re s were were strik strikingly ikin ik i glly different differ errennt fr fro from om th those hose reported hos reporttedd inn the CONFIRM CON ONFIRM ON M study, study dy,,21 in which dy wh 86% of ppatients a ieent at ntss achieved achiev ved the pprimary rima ri m ry y acu acute cute eendpoint, cu n po nd p int,, mostly by ttermination ermi er mina nati na t on of ti of AF rrather athe at heer th tthan an A FCL FC L sl sslowing. owin ow ing. g. Possible Poss Po ssib ss ib blee explanations exp xpla laana nati t on ti onss include incl in c ud cl udee statistical stat st atis at isti is tica ti call ca AFCL variation inherent to small sample size, adverse patient selection due to referral bias of particularly challenging AF patients, and training effect of a new technology. Targeting Rotors in AF Catheter Ablation Rotor ablation did not result in AF termination in this study. One potential explanation is that the mechanism of AF in these patients was not dependent on the rotors identified and targeted for ablation. Even if the FIRM approach does indeed detect rotors, we did not observe regular periodic activation or mathematically distinct electrical activity at these sites, perhaps due to rotor drift or temporal instability, and therefore it is difficult to advocate ablation at these sites.

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Theoretical concerns about rotor ablation in the treatment of AF persist. If FIRMidentified rotors are functional, focal ablation at the center should simply convert functional block to structural block and create fixed anatomic reentry. To effectively treat rotor-driven fibrillation with catheter ablation, a line of conduction block should be created from the rotor core to an anatomic barrier. One mechanism by which focal ablation might be helpful is to increase the range over which the rotor core meanders, which could result in rotor collision with a tissue boundary, and hypothetically terminate spiral reentry.22 However, even this explanation does not hold when the rotor meanders at baseline. Study Limitations This study is limited by a relatively small sample size, resulting in limited powerr to o ddetect etec et ectt sm ec small differences. However, independent differen e ces. Ho H wever, this is the largest independe we ent detailed quantitative ve analysis to date of FIRM-identified FIRM FI RM-identif RM iffie iedd rotor roto ro or sites, site si tes, te s, and nd there ther th eree was er wa no tr ttrend endd towards towa waard rdss unique u iq un que ue rrotor o or ssite ot i e ch it char characteristics arac ar acte ac t riist te stic icss that ic tha might migh migh ght be confi confirmed f rm med inn a larg larger ger study study. y. T These heese we w were re tthe hee ini initial niti ni tial ca ti cases asess pperformed erform rm med using using tthe he F FIRM IR RM system ystem aatt ou oourr in institution. nst s itutio io on. n Altho Although oug ugh it is possible p ssib po iblee that ib tha hatt moree exp experience perienc ncce wouldd have ve yyielded ielded better mapping mapp ma ppin pp ingg and and ab abla ablation laati tion on rresults, esul es u ts ul ts,, so some me of of th tthese esee procedures es proc pr oced oc edur ed ures ur es w were eree pe er perf performed rfor rf orme or medd by a ddeveloper me evel ev e op el oper er ooff th tthee FIRM technology, and most had an experienced FIRM operator onsite as an advisor. One limitation inherent in approaches requiring mapping during AF is that many paroxysmal patients require induction of AF, which may spontaneously terminate even in the absence of ablation. Importantly, since most patients had PVI as well as FIRM-guided ablation, this study did not examine the effects of rotor ablation alone. Finally, this study examines only quantitative characteristics of rotor sites and acute ablation outcomes. Prospective studies of long-term outcomes are required to fully evaluate this technology.

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DOI: 10.1161/CIRCEP.115.002721

Conclusions Systematic quantitative analysis of FIRM-identified rotor sites did not reveal distinctive electrophysiologic features or rotational activity. Catheter ablation of these sites resulted in AF termination or organization in a small minority of patients (17%). FIRM mapping and ablation requires further validation in larger prospective randomized trials, to compare acute procedural outcomes and long-term clinical efficacy of this approach to conventional ablation.

Acknowledgments: We wish to thank Richard Nagel (St Jude Medical) for his invaluable assistance compiling the electroanatomic mapping data for this study. Conflict of Interest Disclosures: None. References: Re efe ferrences re s: JP, Hammill 11. Piccini Pi Haammilll BG, BG, Sinner Sin nner MF,, Jensen Jensen en PN, PN N, Hernandez Herrna nand ndezz AF, nd F, Heckbert Heckb kber kb ertt SR, SR, Benjamin Beenj njam min EJ, EJ, Curtis prevalence mortality among Cu urttis LH. Incidence Inc ncid den nce aand nd pre eva vale l ncce off aatrial le t iaal fibri tr ffibrillation i illaation on and nd aassociated s oci ss ociate t d mort te m o tal alit i y am it mong ong Medicare 1993-2007. Medi diicaare bbeneficiaries, enef effici iciari iariies es, 19 1993-2 200 0077. Circc Cardiovasc Car arddiov di vasc Qual Q all Outcomes. Qu Out utcome t mess. 2012;5:85-93. 2012 20 12;5 12 ; :8 85-93 93. 93 M,, JJais P,, Shah 2. Haissaguerre Haissa sagu sa gueerre gu erre M aiss P ai Sha hahh DC, DC Takahashi Taka Ta kaha ka hash ha shi A, sh A, Hocini Hoc ocin inii M, in M, Quiniou Qui uini niou ni ou G, G, Garrigue Garr Ga rrig rr igue ig ue S, S, Le A,, L Lee M Metayer P,, C Clementy Spontaneous initiation Mo Mouroux A ettayer P lementy t JJ.. S pontaneous t iniitiiati tion off atrial attriiall fibrillation fibbril fi illlati il tion i by by ectopic ecttopic i beats originating in the pulmonary veins. N Engl J Med. 1998;339:659-666. 3. Brooks AG, Stiles MK, Laborderie J, Lau DH, Kuklik P, Shipp NJ, Hsu LF, Sanders P. Outcomes of long-standing persistent atrial fibrillation ablation: a systematic review. Heart Rhythm. 2010;7:835-846. 4. Tilz RR, Rillig A, Thum AM, Arya A, Wohlmuth P, Metzner A, Mathew S, Yoshiga Y, Wissner E, Kuck KH, Ouyang F. Catheter ablation of long-standing persistent atrial fibrillation: 5-year outcomes of the Hamburg Sequential Ablation Strategy. J Am Coll Cardiol. 2012;60:1921-1929. 5. Calkins H. Catheter ablation to maintain sinus rhythm. Circulation. 2012;125:1439-1445. 6. Atienza F, Almendral J, Jalife J, Zlochiver S, Ploutz-Snyder R, Torrecilla EG, Arenal A, Kalifa J, Fernandez-Aviles 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. 2009;6:33-40. 16 Downloaded from http://circep.ahajournals.org/ at University of Manitoba Libraries on June 10, 2015

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7. Cuculich PS, Wang Y, Lindsay BD, Faddis MN, Schuessler RB, Damiano RJ, Jr., Li L, Rudy Y. Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. Circulation. 2010;122:1364-1372. 8. Haissaguerre M, Hocini M, Denis A, Shah AJ, Komatsu Y, Yamashita S, Daly M, Amraoui S, Zellerhoff S, Picat MQ, 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;130:530-538. 9. Ganesan AN, Kuklik P, Lau DH, Brooks AG, Baumert M, Lim WW, Thanigaimani S, Nayyar S, Mahajan R, Kalman JM, Roberts-Thomson KC, Sanders P. Bipolar electrogram shannon entropy at sites of rotational activation: implications for ablation of atrial fibrillation. Circ Arrhythm Electrophysiol. 2013;6:48-57. 10. Narayan SM, Krummen DE, Enyeart MW, Rappel WJ. Computational mapping identifies localized mechanisms for ablation of atrial fibrillation. PLoS One. 2012;7:e46034. 11. Shivkumar K, Ellenbogen KA, Hummel JD, Miller JM, Steinberg JS. Acute term ttermination erm rmin inat in atio at ionn off io sources: human atrial fibrillation by identification and catheter ablation of localized rotors and and so sour urce ur ces: ce s: rotor first multicenter m lticen mu nter experience e perience of focal impulse and ro ex oto t r modulation (FIRM) (FIRM M) ablation. J Cardiovasc Ca ard rdio iovascc Electrophysiol. io Elect ctrrophysiol. 2012;23:1277-1285. ct 12.. Miller V,, Da Daubert Day Ellenbogen KA, Hummel 112 M ller JM, Kowal Mi Kow wal RC, RC, Swarup Sw warupp V Daube ertt JP, Daoud Daou ouud EG EG,, Da ay JD, E lllenb lenb nboogen K A, H umme mel me JD, Krummen Narayan SM, Reddy Shivkumar JD D, Baykaner B ykanerr T, K Ba rum mmen DE DE,, Nara raya ra yaan SM M, R edddyy VY VY, Sh hivkuumar K,, Steinberg Steeinb inberg JS, JS, S, Wheelan Wheelan an KR. outcomes focal impulse rotor modulation KR R. Initial Init In itia it iall independent ia inde in depe de pend pe nden nd ent ou en outcom omes om e ffrom rom m fo foca call im ca impu pulsse and pu and ro roto to or mo modu dula du lati la tionn ablation ti abl blat atio at ionn for io forr atrial atri at rial ri al fibrillation: multicenter FIRM Cardiovasc 2014;25:921-929. fibrillation on: mult on lttic i ente teer FI F RM rregistry. egistry. eg y J Card rdio rd ova vasc s Electrophysiol. sc Elect ctroph ct p ys y io ol. 2014;2 ;25: ;2 5 9221-929. 13. RA, Pertsov Spatial organization 13 3. Gray Gray R A, P erts er tsov ts ov AM, AM, Jalife Jal a if ifee J. S pati pa t al ti a and andd ttemporal empo em pora po rall or ra orga gani ga niza zati za t on during ti dur urin ingg cardiac card ca rddiaac fibrillation. fibr fi bril br illa il laati t on on.. Nature. 1998;392:75-78. N ature 1998;392:75 78 14. Skanes AC, Mandapati R, Berenfeld O, Davidenko JM, Jalife J. Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart. Circulation. 1998;98:1236-1248. 15. Mandapati R, Skanes A, Chen J, Berenfeld O, Jalife J. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. Circulation. 2000;101:194-199. 16. Narayan SM, Krummen DE, Rappel WJ. Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation. J Cardiovasc Electrophysiol. 2012;23:447-454. 17. Lee G, Kumar S, Teh A, Madry A, Spence S, Larobina M, Goldblatt J, Brown R, Atkinson V, Moten S, Morton JB, Sanders P, Kistler PM, Kalman JM. Epicardial wave mapping in human long-lasting persistent atrial fibrillation: transient rotational circuits, complex wavefronts, and disorganized activity. Eur Heart J. 2014;35:86-97.

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18. de Groot NM, Houben RP, Smeets JL, Boersma E, Schotten U, Schalij MJ, Crijns H, Allessie MA. Electropathological substrate of longstanding persistent atrial fibrillation in patients with structural heart disease: epicardial breakthrough. Circulation. 2010;122:1674-1682. 19. Narayan SM, Jalife J. CrossTalk proposal: Rotors have been demonstrated to drive human atrial fibrillation. J Physiol. 2014;592:3163-3166. 20. Zlochiver S, Yamazaki M, Kalifa J, Berenfeld O. Rotor meandering contributes to irregularity in electrograms during atrial fibrillation. Heart Rhythm. 2008;5:846-854. 21. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol. 2012;60:628-636. 22. Spector P. Principles of cardiac electric propagation and their implications for re-entrant arrhythmias. Circ Arrhythm Electrophysiol. 2013;6:655-661.

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DOI: 10.1161/CIRCEP.115.002721

Table 1: Baseline Characteristics

All patients (n=24)

Acute Procedural Success (n = 12)

No Acute Procedural Success (n = 12)

p value

Age ge

64 ± 10

66 ± 11

61 ± 10

0.33

Male ale gender (%)

14 (61)

9 (75)

5 (42))

0.11 0. 11

Paroxysmal roxysm mal pattern pattern rn off AF A (%)

12 (50)

6 (50)

6 (50)

1.00

7.8 ± 5.5

9.0 ± 4.3

6.5 ± 6.5

0.28

155 (63) (633)

8 (67) (6 )

7 (58) (5 58)

00.69 .669

Number umb mber mb err ooff pr prev previous ev vio iouus A AF F ablati aablations b ionns

11.2 1. 2 ± 1.1 1.

11.4 1. 4 ± 1.3 1..3

0.99 ± 0.9 09 0.

00.29 .229

Number umber of fa failed ailled d aantiarrhythmic ntia nt iarr ia rrhy rr hyth hy th hmi micc dr ddrugs ugss ug

1.7 1. .7 ± 1.0 1.0

1.55 ± 0.9 1. 09 0.

1.88 ± 1.0 1. 1.0

0.41

CHA2DS2-VaSC HA2DS2-VaSC SC score

11.7 1. 7 ± 1.0 1.00

11.8 .88 ± 1.1 1

11.6 1. 6 ± 1.0 10 1.

0.57

LVEF (%)

63 ± 6.9

64 ± 5.7

61 ± 8.0

0.31

LA volume on MRI (ml)

76 ± 32

79 ± 31

73 ± 33

0.64

AF F dduration urrat a ion (years rs from diagnosis)) Prior ior A AF F ablation (%)

Values are n (%) or mean ± standard deviation. LA = Left atrium, LVEF = left ventricular ejection fraction.

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Table 2: Rotor Mapping Results.

All procedures (n=24)

Acute Procedural Success (n = 12)

No Acute Procedural Success (n = 12)

p value

Number mber LA rotors identified

1.6 ± 0.8

1.7 ± 0.9

1.5 1. .5 ± 0.7

00.61

Number mber RA rotors identified

0.6 ± 0.8

0.7 ± 0.9

0.66 ± 0.8 0. 0.8

00.81

54% 54 % ± 15%

56% ± 16 16% 6%

53% ± 15%

00.75

Number mb berr ooff basket electrodes ele lectrodes with adequate adequ q ate atrial electrogram

331 1 ± 17

227 7 ± 18

35 ± 16

00.28

Dominant minaant n frequency at rrotor oto or site sites es ((Hz) Hz)

4.8 4. .8 ± 1.3 1.3

44.8 .8 ± 1.4 4

5.00 ± 1.3 3

00.62

Dominant mina nant na ntt ffrequency r qu re quen en ncy at nnon-rotor onn-roto n- or sites si (H (Hz) Hz) z

4.7 4. .7 ± 1.6 6

4.8 4. .8 ± 1.6 6

4.66 ± 1.7 4. 7

00.06

Shannon nnon entropy entrop opyy at rrotor op otor ot or ssites ites it es

4.8 ± 0.5 4.8 0.5

44.8 4. 8 ± 0.3 03 0.

4.99 ± 0.7 4. 0.7

00.35

Shannon nnon entropy at non-rotor non-rottor si sites ite t s

44.9 .99 ± 0.6 06 0.

44.8 .88 ± 0.5 05 0.

55.0 5. 0 ± 0.6 06 0.

00.08

1 (4%)

0 (0)

1 (8%)

0.34

Proportion portion of of LA L surface sur urface cee area area mapped with basket catheter

Patients with rotational activity or focal source at rotor site on electroanatomic mapping Values are n (%), mean ± SD. LA = Left atrium, RA = Right atrium.

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Table 3: Ablation results.

All procedures (n=24)

Acute Procedural Success (n = 12)

No Acute Procedural Success (n = 12)

p value

Procedure cedure time (min)

358 ± 72

351 ± 70

365 ± 77

0.63

Fluoroscopy roscopy time (min)

68 ± 24

71 ± 24

65 ± 244

00.55 0. .55 55

Total al RF abl ablation blat atio ion time m ((min) m n) mi

41 ± 17

44 ± 18

39 ± 16

0.47

Rotor oto tor R to RF F ablationn ttime ime (min) (min)

20 ± 11

20 ± 12

19 ± 11

0.99

Non-rotor on-rrotor RF ablation tim time me (m (min) minn) n)

222 2 ± 17 7

25 ± 18 25

200 ± 17

0.49 49

AFCL CL L ppre-ablation ree-ab a la lati tion on ((ms) ms))

189 18 89 ± 366

183 ± 255 18

196 19 96 ± 46 4

0.40 0. 40

AFCL CL post-abl post-ablation lati lati t on ((ms) ms)) ms

2077 ± 441 20 1

2155 ± 377 21

1988 ± 46 19

0.36

RF = Radiofrequency, AFCL = AF A cycle length.

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Figure Legends: Figure 1: Left Atrial Basket Catheter Position and Recordings. A: Fluoroscopic image of 64pole Constellation basket catheter in LA with good chamber coverage and equidistant splines. B: Basket catheter with compressed splines, resulting in inadequate coverage of posterior and septal LA. C: Basket catheter with bunched splines, resulting in large areas of unsampled LA endocardium. D: Example of 64 unipolar electrograms recorded simultaneously during AF.

Figure 2: Analysis of Basket Catheter Coverage. A: Electroanatomic map created with Ensite NAVX system. LA surface was segmented to calculate total surface area outside ppulmonary ulmo ul mo ona nary ry y veins (outlined in white), then 1 cm fill threshold was set to calculate surface area ne near arr aany ny basket ba ask sket et electrode elect ctro ct rodee ((colored ro colored area). B: Example of mapped maappped and unmapped unmap ppe p d LA endocardial areas plotted map. p ottte pl t d on electroanatomic electroa oanato oa omic ma map p.

Figure 33:: Qu Quantitative Analysis Atrial Unipolar Electrograms. unipolar Quan anti an tita ti tati ta tive ti ve An Anal alys al y is ooff At ys Atri rial ri al U nipo ni poola larr El Elec ectr ec trog tr ogra og rams ra ms. A: Ra ms Raw w un unip ipol ip olar ol ar ssignal igna ig nall from na single ingle electrode on basket catheter, catheter with red arrows indicating QRS complexes to be filtered out. out B: QRS waveforms are plotted simultaneously to create an aggregated QRS-T complex. C: Remainder signal after QRS-T subtraction shows pure atrial electrical activity.

Figure 4: Frequency Domain and Entropy Analysis Example. Both panels are 8x8 grids representing each electrode of the 64-channel basket catheter from a single patient. In the top panel, the dominant frequency (DF) of each atrial unipolar signal is shown in a color map. The insets contain representative Fourier transforms illustrating similar DF at a FIRM-identified rotor

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DOI: 10.1161/CIRCEP.115.002721

site, and elsewhere in the atrium. The bottom panel illustrates similar Shannon Entropy (ShEn) in a FIRM-identified rotor region and the rest of the left atrium.

Figure 5: Detailed Results of Frequency Domain and Entropy Analysis. A: Histogram of dominant frequency at all rotor and non-rotor sites shows similar frequency distribution. B: Histogram of Shannon entropy at all rotor and non-rotor sites shows similar frequency distribution.

Figure 6: Atrial Electrogram Analysis: Local Activation Time. A: The top tracing is surface ECG lead II, and below is the local EGM from a rotor site recorded by basket catheter. Only cat atthe hetter. ter. O nlyy nl ventricular activation tracing. ventricu c lar ac ctivaati t on can be seen on the local tracin ing. g B: On this unipolar unipola larr recording with voltage 0.06 0. 6 mV, low w amplitude amp mplitu tude tu de atrial atr tria iall EGM EGM can can bee sseen, een, but ee but ut activation act ctiv ct ivat iv atio at i n time io time cannot can anno n t bee accurately no acc ccur urattel ur elyy annotated. with voltage and an nnoota t ted. C:: On n tthis his unipolar unnipollar recording recorrdi d ng wit th volt tag ge 0.28 0.28 mV, mV, atrial atrrial EGM EG GM is is decipherable decip pheeraablle an nd shows hows variable vaari riable cycle cyc ycle length. len engt g h.

Figure 7: Electroanatomic Mapping. A: Sequential activation isochrone maps show disorganized activity with no rotation. B: Rotational activity seen, with change in chirality in sequential activation sequences

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Quantitative Analysis of Localized Sources Identified by Focal Impulse and Roter Modulation Mapping in Atrial Fibrillation Peyman Benharash, Eric Buch, Paul Frank, Michael Share, Roderick Tung, Kalyanam Shivkumar and Ravi Mandapati Circ Arrhythm Electrophysiol. published online April 14, 2015; Circulation: Arrhythmia and Electrophysiology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-3149. Online ISSN: 1941-3084

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