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Organizational Index Mapping to Identify Focal Sources During Persistent Atrial Fibrillation JULIAN W. E. JARMAN, MD(Res.), M.R.C.P,∗ TOM WONG, M.D., F.R.C.P.,∗ PIPIN KOJODJOJO, Ph.D., M.R.C.P.,∗ ,† HILMAR SPOHR, M.Sc., M.B.B.S.,∗ JUSTIN E.R. DAVIES, Ph.D., M.R.C.P.,∗ ,† MICHAEL ROUGHTON, M.Sc.,∗ DARREL P. FRANCIS, M.D., F.R.C.P.,∗ ,† PRAPA KANAGARATNAM, Ph.D., M.R.C.P.,∗ ,† MARK D. O’NEILL, DPHIL, M.R.C.P., F.H.R.S.,∗ VIAS MARKIDES, M.D., F.R.C.P.,∗ D. WYN DAVIES, M.D., F.R.C.P., F.H.R.S.,∗ ,† and NICHOLAS S. PETERS, M.D., F.R.C.P., F.H.R.S.∗ ,† From the ∗ Imperial College London, UK; and †St. Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK
Organizational Index Maps of AF. Introduction: Localized rotors have been implicated in the mechanism of persistent atrial fibrillation (AF). Although regions of highest dominant frequency (DF) on spectral analysis of the left atrium (LA) have been said to identify rotors, other mechanisms such as wavefront collisions will sporadically also generate an inconsistent distribution of high DF. We hypothesized that if drivers of AF were present, their distinctive spectral characteristics would result more from their temporal stability than their high frequency. Methods and Results: Ten patients with persistent AF underwent LA noncontact mapping. Following subtraction of far-field ventricular components, noncontact electrograms at 256 sites underwent fast Fourier transform. Mean absolute difference in DF between 5 sequential 7-second segments of AF was defined as the DF variability (DFV) at each site. Mean ratio of the DF and its harmonics to the total power of the spectrum was defined as the organizational index (OI). Mean DFV was significantly lower in organized areas (OI > 1 SD above mean) than at all sites (0.34 ± 0.04 vs 0.46 ± 0.04 Hz; P < 0.001). When organized areas were ablated during wide-area circumferential ablation, AF organized in remote regions (LA appendage OI ablated vs unablated: +0.21 [0.06–0.41] vs −0.04 [−0.14–0.05]; P = 0.005). Conclusions: At sites of organized activation, the activation frequency was also significantly more stable over time. This observation is consistent with the existence of focal sources, and inconsistent with a purely random activation pattern. Ablation of such regions is technically feasible, and was associated with organization of AF in remote atrial regions. (J Cardiovasc Electrophysiol, Vol. 25, pp. 355-363, April 2014) atrial fibrillation, catheter ablation, dominant frequency, Fourier analysis, rotors, spectral analysis Introduction Modern understanding of persistent atrial fibrillation (AF) has evolved from the multiple reentrant wavelet hypothesis to acknowledge experimental data in animals1-2 and humans,3-5 suggesting fibrillatory conduction away from high-frequency
This work was supported by the British Heart Foundation PG/04/041, RG/10/11/28457, NIHR Biomedical Research Centre funding, and the ElectroCardioMaths Programme of the Imperial BHF Centre of Research Excellence. N.S. Peters, T. Wong, and V. Markides have received research grants from St. Jude Medical. D.W. Davies participated on research grants supported by Medtronic, Boston Scientific, and Rhythmia Medical; reports honoraria from Boston Scientific and Rhythmia Medical; reports serving as a consultant for Medtronic; holds stock options in Rhythmia Medical. Other authors: No disclosures. Address for correspondence: Nicholas S. Peters, M.D., F.R.C.P., F.H.R.S., St. Mary’s Hospital, Praed Street, London, W2 1NY United Kingdom. Fax: +44-20-7886-2291; E-mail: [email protected] Manuscript received 28 July 2013; Revised manuscript received 17 November 2013; Accepted for publication 2 December 2013. doi: 10.1111/jce.12352
localized reentrant circuits, or “‘rotors,” which may represent discrete drivers of AF.6 The rotor hypothesis of persistent AF maintenance provided the theoretical underpinning for recent interest in highfrequency activity as a target for catheter ablation.7-9 Highfrequency atrial activation was considered the hallmark of rotor sites. Targeting of such sites was attempted initially by ablating at the sites of complex fractionated atrial electrograms (CFAEs).7-10 More recently, with the heterogenous nature of CFAE sites becoming apparent, spectral analysis was used to more accurately identify high-frequency activation and high dominant frequency (DF) adopted to target ablation to rotor sites.8,9,11 However, following initial reports of remarkable therapeutic success,7 later randomized trial results of CFAE ablation were disappointing,12-15 while data on high DF ablation outcomes are limited and conflicting.8,9,16,17 DF may inaccurately represent underlying activation rates during AF in epicardial18 and endocardial19 spectral mapping. Spuriously high DF values may be calculated in regions of wavefront collision or turning,19 and thus bystander regions distant from rotors may theoretically show higher DF than a rotor. Additionally, systematic mapping of simultaneous global left atrial DF found DF maps highly spatiotemporally unstable, calling into question their utility for guiding ablation.20,21
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We hypothesized that rotors, or indeed any focal sources, whether reentrant or automatic, need not display the highest DF but, in keeping with other focal and reentrant tachycardias,5 would instead be characterized by the association of a narrow frequency range approximating a single cycle length, referred to as “organization,” and relatively constant frequency DF magnitude in successive time periods, referred to as “temporal stability.” Although transient organization of activation may occur probabilistically, organized regions would not be expected to have greater temporal stability if underlying activation was truly random. To test the hypothesis that organized areas have less variability of DF magnitude over time than the remaining left atrium, and thus may identify focal sources as targets for ablation in persistent human AF, we examined the effects of left atrial ablation on spectral analysis of simultaneous, high-density noncontact (EnSiteArrayTM , St. Jude Medical, St. Paul, MN, USA) endocardial mapping as previously validated in the animal22 and human atrium.21,23,24 Methods Study Patients Consecutive patients referred for first ablation with symptomatic drug-refractory AF that had been persistent for at least 2 years were studied. Antiarrhythmic drugs were stopped at least 5 half-lives preoperatively and no patient was taking amiodarone. The study protocol was approved by the local ethics committee and all procedures were carried out under conscious sedation with written informed consent. Noncontact Mapping A noncontact multielectrode array (EnSite Array; St. Jude Medical) and a 4-mm-tip irrigated ablation catheter (Biosense-Webster, Diamond Bar, CA, USA) were deployed transseptally into the LA, the former anchored by a guidewire in the left superior pulmonary vein. The noncontact system has previously been described in detail.21,23-25 Following detailed left atrial geometry acquisition, persistent AF was recorded with the noncontact system to analyze off-line. Filter settings of noncontact electrograms were 1–150 Hz.16,21 Patients then underwent catheter ablation with the operator blinded to the results of spectral analysis. Subsequently, further noncontact mapping data were collected after all ablation was complete. Noncontact mapping data were subjected to spectral analysis to contrast the characteristics of baseline and postablation persistent AF. Off-Line Signal Processing Noncontact unipolar electrograms sampled at 1,200 Hz were exported from 256 evenly distributed sites on the reconstructed LA surface in temporally sequential 7-second segments.16,21 Off-line analysis used customized software programmed in the MATLAB (Mathworks, Natick, MA, USA) environment with signals processed through the following steps. (1) Subtraction of far-field ventricular components: the averaged far-field ventricular component of the unipolar electrogram at each of the 256 sites was digitally subtracted from the raw signal using a semi-automated algorithm based on a QRS cancellation technique.21 (2) Hanning windowing: the ventricular-subtracted data from each of the
256 points within each 7-second segment were subjected to Hanning windowing to reduce the effect of discontinuity at the extremes of the segment. (3) Fourier transformation: the processed electrograms were then subjected to fast Fourier transform algorithm. Definitions The resultant power frequency spectra in the physiologically relevant 3–20 Hz range at each site were examined using the following definitions. DF: the frequency with highest power on the power frequency spectrum for a 7-second segment. Mean DF: the mean of the 5 DF values identified by analysis of 5 temporally consecutive segments of 7 seconds of AF at a single site. DF variability (DFV): the absolute difference between the DF values in successive pairs of the 5 7-second segments was calculated at each site, and the mean of these 4 values defined the DFV at that site. Organzsational index (OI): the area under the DF peak and its harmonics (within a 0.75 Hz window) in the power frequency spectrum for each 7-second segment at a single site was divided by the total area under the spectrum (Fig. 1)—the mean of the calculated values for the 5 segments was defined as the OI at that site.2 These definitions are illustrated in Figure 2. OI maps and Definition of Organized Areas OI values at 256 sites were plotted on a 3-dimensional virtual LA surface, creating an OI map (Fig. 3). Regions where all OI values were more than 1 standard deviation greater than the mean OI of all sites were defined as organized areas (Fig. 4). Their location was categorized using 12 predefined anatomical areas: 4 pulmonary vein (PV) antra, remaining posterior wall (excluding PV antra), roof, left atrial appendage, base of left atrial appendage, anterior wall, septum, lateral wall and floor. Spatiotemporal Stability: Reproducibility of OI Maps The strength of agreement between OI maps generated utilizing data from 2 successive 35-second time periods prior to ablation was evaluated by calculating the reliability coefficient. This value assesses the proportion of the variance between all OI values in all maps that is attributable to the variation between the OI values at the 256 different sites on individual maps. Thus, a low coefficient indicates that there is a high degree of variance between OI values recorded at individual sites over successive time periods, relative to the degree of variance between the OI values recorded at different sites in a single time period, and thus that the maps are not spatiotemporally stable. Catheter Ablation Using the irrigated 4-mm-tipped catheter, patients underwent wide-area circumferential ablation (WACA) with consistent, anatomically determined linear ablation lesions encircling the left- and right-sided pulmonary veins in pairs. Encircling lesions were joined by a linear roof lesion, and another linear lesion connected the left-sided encircling lesion to the mitral valve annulus. Power was limited to 35 W, and on the posterior wall to 25 W. Subsequently, patients were converted to sinus rhythm with external direct current cardioversion.
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Figure 1. Calculation of organizational index. A band 0.75 Hz either side of the dominant frequency in a power frequency spectrum (top = first). Area under the band is calculated (second). Area under the first harmonic of the dominant frequency is added (third). Resultant area is divided by the total area under the power frequency spectrum (fourth).
Ablation of Organized Areas and Definition of Remote Effect on OI The spatial relationship between organized areas on the baseline OI map and subsequent WACA lesions was examined retrospectively. When highest OI within an organized area was < 1 virtual electrode distance from an ablation line, this organized area was considered ablated (WACAOI group); otherwise, all organized areas were considered un-ablated (WACA-only group). In order to assess the effect of ablation on OI at a site remote from the lesions, the perimeter of the left atrial appendage (LAA) was located with the mapping catheter and labeled during the procedure, and 6 virtual electrodes from within this area were defined as the LAA sample used to examine the impact of ablation on OI in the LAA before and after ablation. Statistical Analysis Normally distributed continuous data were expressed as mean ± standard deviation, and other continuous data as median and range. Comparison between groups uses the paired
or unpaired Student t-test for normally distributed data, or otherwise the Wilcoxon rank sum, Mann–Whitney U, or Fisher’s exact tests. Preferential anatomical distribution of organized areas was assessed with the chi-square test. The correlation was assessed with the Pearson correlation coefficient. The reliability coefficient (R), the true variance as a proportion of the total variance, was used to assess agreement in OI values at multiple locations on a map between 2 time periods. Two-sided P values < 0.05 were considered significant. Results Study Population and Ablation Procedure Ten patients completed the protocol (6 men; age 58 ± 10 years): AF was long-lasting persistent in all patients (median duration 24 months (range 12–56 months)). LA diameter was 47 ± 8 mm and left ventricular ejection fraction 51 ± 10% (Table 1). There was no procedural complication. All patients required external cardioversion from AF to sinus rhythm at the end of the procedure.
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Figure 2. Definitions employed. A stylized drawing of an electrogram at a single left atrial site is used to illustrate how the mean dominant frequency (DF), dominant frequency variability (DFV), and organizational index (OI) at that site are calculated, using the values for DF and OI calculated at 5 sequential 7-second segments of AF.
Characteristics of Organized Areas We found 27 organized areas (median 2, range 2–4, per patient), with median surface area 7 cm2 (range 2–18 cm2 ), representing median 5% (range 1–10%) of total LA surface area. Among all patients at baseline, median lowest OI was 0.17 (range 0.10–0.28) and median highest OI 0.66 (range 0.50–0.75), and median difference between these values 0.44 (range 0.35–0.58). By definition, mean OI in organized areas was higher (0.51 ± 0.02) than mean OI of all 256 sites (0.41 ± 0.02). Organized areas were frequently located at the PV antra (44%, P = 0.32 compared with non-PV areas) (Fig. 5). Median reliability coefficient between successive 35-second OI maps was 0.47 (range 0.29–0.70), indicating moderate agreement between maps (Fig. 6).
Relationship Between Organization and Temporal Stability Dominant frequency variability (DFV) in organized areas was lower than DFV among all LA sites in every patient and for the whole group (0.34 ± 0.04 vs 0.46 ± 0.04 Hz; P < 0.001), indicating significantly greater temporal stability of DF in these areas, and consistent with our hypothesis. Relationship Between Organization and Dominant Frequency Among all patients, mean DF among sites in organized areas (6.31 ± 0.18 Hz) was modestly but significantly higher than among all LA sites (6.21 ± 0.17 Hz; P = 0.003).
Figure 3. Organizational index map. In a right superior view, OI values are plotted alongside virtual electrodes colored according to a normalized scale with interpolation between electrodes. Seven-second ventricular-subtracted noncontact electrograms are displayed on left. Their power frequency spectra are displayed underneath with 3 – 15 Hz range on the horizontal axis. Values for OI, mean DF, and DFV (calculated from 35 seconds of data) displayed below. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
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Figure 4. Map of organized areas. The same map as Figure 3, with color bar set to only color areas where OI is >1 standard deviation above the mean. A single organized area is seen on the left atrial roof. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
TABLE 1 Patient Characteristics
Male sex Age at time of study (years) LA size (mm) LVEF (%) Time in persistent AF (months)
values compared to other LA sites (mean LA OI 0.43 [range 0.33–0.58], highest LA OI 0.66 [range 0.51–0.79]), whereas following ablation, due to a rise in overall LA OI, their OI was close to the LA mean (mean LA OI 0.54 [0.37–0.85], highest LA OI 0.79 [range 0.6–0.95]).
All Patients
WACA-OI WACA-Only Group Group P Value
4/10 58 ± 10
2/6 62 (42–71)
4/4 57 (47–67)
0.071 0.762
Location of Data Samples and Validation of EnSite System During Atrial Tachycardia
47 ± 8 45 (41–50) 51 ± 10 54 (39–65) 24 (12–56) 22 (12–32)
47 (43–67) 51 (31–54) 24 (19–56)
0.476 0.352 0.610
Data points among all patients were 29.6 ± 9.8 mm from the center of the array, with 85% of all points located < 40 mm from the center. In 1 WACA-OI patient, AF converted to atrial tachycardia (AT) during WACA, before subsequently degenerating again to highly organized AF. This provided a useful opportunity to validate the EnSite system as used in our protocol. Contact electrograms revealed a stable cycle length of 222 milliseconds during AT. Noncontact data during AT were used to create a DF map following subtraction of the far-field ventricular components (Fig. 8). Two hundred fortysix of 256 sites (96%) show DF 4.5 Hz, confirming correct interpretation of the underlying atrial cycle length. At the remaining 10 sites, DF was 9.1 Hz: these sites on the posterior wall overlay ablation lesions encircling the pulmonary veins and the DF values calculated reflected double counting of the underlying atrial activation rate at these lines of block.
AF = atrial fibrillation; LA = left atrial; LVEF = left ventricular ejection fraction. Data are presented as mean ± standard deviation, or median (range). P values are for differences between WACA-OI and WACA-only groups.
However, there was no overall correlation between mean DF and OI (mean correlation coefficient 0.17 ± 0.06). OI Ablation and Impact on Remote Regions Among 10 patients undergoing WACA, 6 had ablation of organized areas (WACA-OI group) and 4 did not (WACAonly group). There were no significant differences between the patient characteristics of the 2 groups (Table 1). Only in the WACA-OI group was there an increase in OI in the LAA, and therefore spatially remote from the ablation; WACA-OI group (0.21 [range 0.06–0.41]) compared with the WACAonly group (−0.04 [range −0.15–0.05]; P = 0.005) (Fig. 7). The OI in sites adjacent to where highest OI was ablated in the WACA-OI group did not change significantly (from 0.55 [range 0.34–0.74] to 0.54 [0.28–0.89]; [P = 0.911]). However, prior to ablation, these sites had relatively high OI
Discussion The principle finding of this study was that, consistent with our hypothesis regarding the expected spectral characteristics of focal sources, including localized reentrant
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Figure 5. Regional distribution of organized areas. Left atrial geometry displayed in posteroanterior (left) and anteroposterior (right) projections. LAA = left atrial appendage; LIPV = left interior pulmonary vein; LSPV = left superior pulmonary vein; PV = pulmonary vein; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
Figure 6. Temporally sequential 35-second organizational index maps. Right anterior oblique cranial projection. OI values are plotted alongside virtual electrodes and organized areas (OI > 1 standard deviation above the mean) are colored using normalized scales. Organized areas remain in relatively stable locations. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
“rotors,” driving persistent AF, areas of organized activation were associated with significantly greater temporal stability of DF than in other areas. This previously unreported finding, of areas that are both organized and spatiotemporally stable, would not be expected with a purely randomly distributed underlying activation pattern and is consistent with the presence of focal sources driving AF in these patients. Additionally, where ablation fortuitously occurred in organized areas, this was associated with greater organization of AF in remote regions, consistent with elimination of focal sources. Following ablation in organized areas, the degree of organization of adjacent sites returned to the average for the atrium overall.
Spectral Mapping of AF With the realization that pulmonary vein isolation alone is usually an ineffective treatment for persistent AF,26 recent investigation has focused on identifying (ideally discrete) targets to guide additional left atrial substrate modification. Evidence of the existence of high-frequency sources, which may maintain AF,1-5,27,28 including data from endocardial contact mapping27,28 and data suggesting a reentrant mechanism in humans,4 naturally suggested these phenomena as possible targets. The presence of activation frequency gradients from the drivers to surrounding atrial tissue informed the
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Figure 7. Organizational index (OI) maps with and without OI ablation. Patient A has highest OI anterior to the right superior pulmonary vein at baseline (A1). The region is transected by WACA (black line). After all ablation (A2), mean appendage OI has increased to 0.86. Patient B has highest OI on the anterior wall at baseline (B1). WACA lesions do not encroach on this area. After all ablation (B2) over an hour later, highest OI remains present and mean appendage OI has reduced to 0.35. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
development of spectral mapping to systematically identify areas with high DF, predicated on the assumption that DF would proxy underlying activation rates. However, the efficacy of prospective targeting of such sites during AF has yet to be proven.
Limitations of DF Mapping DF can sometimes misrepresent underlying activation rates during AF in both epicardial18 and endocardial19,29 studies. This can occur when an electrogram’s amplitude and rate vary simultaneously, or through “double counting” at points where wavefronts collide or turn. All of these are characteristically widespread and common phenomena in AF and would be consistent with the observation that sites of high or “highest” DF values are spatiotemporally unstable,20,21 and the absence of convincing data showing a beneficial effect of targeting sites of high DF in patients with persistent AF. In 1 nonrandomized trial where DF ablation was prospectively applied in 18 patients with persistent AF,8 all patients underwent additional circumferential pulmonary vein isolation (PVI), yet only 50% maintained sinus rhythm after 8 months, a result comparable with outcomes seen when circumferential PVI has been used alone in other studies.30 When DF ablation was combined with PVI in another trial the results were not better than in a control group undergoing PVI alone.17
Organizational Index Mapping For these reasons we hypothesized that highest DF was not a necessary spectral characteristic of a focal source driving persistent AF. We further hypothesized that, in keeping with the spectral characteristics of other focal or reentrant tachycardias,5 they would principally be characterized by the association of organized activation (a narrow frequency range) with relative temporal stability of their DF (relatively consistent frequency magnitude). This combination of characteristics, which have formed part of the definition of rotors in previous studies,2,3,5 would not be expected if created by continuously varying bystander sites of wavefront collision. The central finding of this study, that low DF variability is systematically associated with areas of high OI, has not previously been reported and is consistent with the existence of focal sources during persistent AF. It would not be expected with a randomly determined activation pattern. The finding that OI maps, unlike DF maps, have moderate reproducibility between 35 second periods is more consistent with the properties expected of stable drivers. Unlike DF maps that lack spatiotemporal stability (Kappa values −0.07–0.22),20,21 OI maps have moderate reproducibility (median Kappa 0.47) and thus may have greater utility to guide ablation to particular regions of the atria, although accuracy, at least using the techniques in this study, is still limited. Thus, although the findings of the present study support the concept that fixed regions of high organizational index
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Figure 8. Mean dominant frequency map of atrial tachycardia. Mean DF values are shown at each site and color coded to a normalized scale without interpolation between points. A single value of 4.5 Hz, corresponding exactly to tachycardia cycle length 222 milliseconds, is seen at all sites, with the exception of 10 sites where 9.1 Hz is shown: these reflect double counting over ablation lesions posterior to the RIPV and LSPV. LAO = left anterior oblique projection; LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein; MVA = mitral valve annulus; PA = posteroanterior projection; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
identify sites of stable focal sources during AF, this study does not prove the existence of rotors and other possible explanations include localized bystander channels of regular activation determined by local refractory periods. We found that ablation incorporating sites of high OI was associated with increasing organization of the left atrial appendage, a region spared from direct ablation, in all patients. This was not observed in patients in whom OI was not ablated during WACA. If OI ablation reduces the number of active focal sources, it would be consistent with activation in a remote region becoming incrementally more organized; however, in this small number of patients, this finding should be interpreted with caution. Recently, reentrant sources have been convincingly identified in human atria by applying an alternative spectral analysis technique, the Hilbert transform, combined with wave similarity analysis, to high-density contact mapping data.31-33 The mean rotor cycle length observed in persistent AF was 163 milliseconds, equivalent to 6.1 Hz and similar to the mean DF of 6.3 Hz in our study.31 There was no correlation between the location of focal sources and that of highfrequency CFAEs.32 Focal ablation at these sites sometimes terminated AF and appeared to improve the success of widearea circumferential pulmonary vein isolation,33 even when performed unintentionally.34 Limitations There are many questions that could not be answered in a study of this design. These include the lack of contact data, right atrial activation data, and how changes in autonomic tone may have affected OI maps. Additionally, low OI values might theoretically be seen in regions distant from the center of the multielectrode array due to lower signal-tonoise ratio. In this study 15% of data samples were >40 mm from the array center, beyond which data quality may deteriorate;35 however, organized areas were found in almost
all atrial areas, commonly including the pulmonary vein ostia and left atrial appendage, which may be in relatively polar positions relative to the array. Finally, the definition of organized areas employed (OI > 1 SD above the mean OI) made it inevitable that organized areas would be described in all patients—therefore, the relationship between organization and lower DF variability described cannot provide evidence of the frequency with which true rotors or focal sources are found among a group of patients. Conclusions Simultaneous spectral mapping throughout the human left atrium during persistent AF reveals that regions of organized activation have greater temporal stability of their DF than other areas, and also exhibit considerable spatiotemporal stability. This finding is consistent with the existence of focal sources during persistent AF. Ablation of such areas guided by noncontact mapping technology is technically feasible and when ablated in this study, was associated with the organization of AF in remote atrial regions. References 1. 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. 2. Kalifa J, Tanaka K, Zaitsev AV, Warren M, Vaidyanathan R, Auerbach D, Pandit S, Vikstrom KL, Ploutz-Snyder R, Talkachou A, Atienza F, Guiraudon G, Jalife J, Berenfeld O: Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation 2006;113:626-633. 3. Sahadevan J, Ryu K, Peltz L, Khrestian CM, Stewart RW, Markowitz AH, Waldo AL: Epicardial mapping of chronic atrial fibrillation in patients: Preliminary observations. Circulation 2004;110:3293-3299. 4. Atienza F, Almendral J, Moreno J, Vaidyanathan R, Talkachou A, Kalifa J, Arenal A, Villacast´ın JP, Torrecilla EG, S´anchez A, PloutzSnyder R, Jalife J, Berenfeld O: Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: Evidence for a reentrant mechanism. Circulation 2006;114:2434-2442.
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5. Ryu K, Sahadevan J, Khrestian CM, Stambler BS, Waldo AL: Use of fast Fourier transform analysis of atrial electrograms for rapid characterization of atrial activation-implications for delineating possible mechanisms of atrial tachyarrhythmias. J Cardiovasc Electrophysiol 2006;17:198-206. 6. Waldo AL: Mechanisms of atrial flutter and atrial fibrillation: Distinct entities or two sides of a coin? Cardiovasc Res 2002;54:217-229. 7. Nademanee K, McKenzie J, Kosar E, Schwab M, Sunsaneewitayakul B, Vasavakul T, Khunnawat C, Ngarmukos T: A new approach for catheter ablation of atrial fibrillation: Mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044-2053. 8. Atienza F, Almendral J, Jalife J, Zlochiver S, Ploutz-Snyder R, Torrecilla EG, Arenal A, Kalifa J, Fern´andez-Avil´es F, Berenfeld O: Realtime 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. 9. Sanders P, Berenfeld O, Hocini M, Ja¨ıs P, Vaidyanathan R, Hsu LF, Garrigue S, Takahashi Y, Rotter M, Sacher F, Scav´ee C, Ploutz-Snyder R, Jalife J, Ha¨ıssaguerre M: Spectral analysis identifies sites of highfrequency activity maintaining atrial fibrillation in humans. Circulation 2005;112:789-797. 10. Monir G, Pollak SJ: Consistency of the CFAE phenomena using custom software for automated detection of complex fractionated atrial electrograms (CFAEs) in the left atrium during atrial fibrillation. J Cardiovasc Electrophysiol 2008;19:915-919. 11. Mansour M: Highest dominant frequencies in atrial fibrillation: A new target for ablation? J Am Coll Cardiol 2006;47:1408-1409. 12. Oral H, Chugh A, Yoshida K, Sarrazin JF, Kuhne M, Crawford T, Chalfoun N, Wells D, Boonyapisit W, Veerareddy S, Billakanty S, Wong WS, Good E, Jongnarangsin K, Pelosi F Jr, Bogun F, Morady F: A randomized assessment of the incremental role of ablation of complex fractionated atrial electrograms after antral pulmonary vein isolation for long-lasting persistent atrial fibrillation. J Am Coll Cardiol 2009;53:782-789. 13. Oral H, Chugh A, Good E, Wimmer A, Dey S, Gadeela N, Sankaran S, Crawford T, Sarrazin JF, Kuhne M, Chalfoun N, Wells D, Frederick M, Fortino J, Benloucif-Moore S, Jongnarangsin K, Pelosi F Jr, Bogun F, Morady F: Radiofrequency catheter ablation of chronic atrial fibrillation guided by complex electrograms. Circulation 2007;115:2606-2612. 14. Khaykin Y, Skanes A, Champagne J, Themistoclakis S, Gula L, Rossillo A, Bonso A, Raviele A, Morillo CA, Verma A, Wulffhart Z, Martin DO, Natale A: A randomized controlled trial of the efficacy and safety of electroanatomic circumferential pulmonary vein ablation supplemented by ablation of complex fractionated atrial electrograms versus potentialguided pulmonary vein antrum isolation guided by intracardiac ultrasound. Circ Arrhythm Electrophysiol 2009;2:481-487. 15. Oral H, Chugh A, Good E, Crawford T, Sarrazin JF, Kuhne M, Chalfoun N, Wells D, Boonyapisit W, Gadeela N, Sankaran S, Kfahagi A, Jongnarangsin K, Pelosi F Jr, Bogun F, Morady F: Randomized evaluation of right atrial ablation after left atrial ablation of complex fractionated atrial electrograms for long-lasting persistent atrial fibrillation. Circ Arrhythm Electrophysiol 2008;1:6-13. 16. Lin YJ, Tai CT, Kao T, Tso HW, Huang JL, Higa S, Yuniadi Y, Huang BH, Liu TY, Lee PC, Hsieh MH, Chen SA: Electrophysiological characteristics and catheter ablation in patients with paroxysmal right atrial fibrillation. Circulation 2005;112:1692-1700. 17. Verma A, Lakkireddy D, Wulffhart Z, Pillarisetti J, Farina D, Beardsall M, Whaley B, Giewercer D, Tsang B, Khaykin Y: Relationship between complex fractionated electrograms (CFE) and dominant frequency (DF) sites and prospective assessment of adding DF-guided ablation to pulmonary vein isolation in persistent atrial fibrillation (AF). J Cardiovasc Electrophysiol 2011;22:1309-1316. 18. Narayan SM, Krummen DE, Kahn AM, Karasik PL, Franz MR: Evaluating fluctuations in human atrial fibrillatory cycle length using monophasic action potentials. Pacing Clin Electrophysiol 2006;29:1209-1218. 19. Ng J, Kadish AH, Goldberger JJ: Effect of electrogram characteristics on the relationship of dominant frequency to atrial activation rate in atrial fibrillation. Heart Rhythm 2006;3:1295-1305.
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20. Habel N, Znojkiewicz P, Thompson N, M¨uller JG, Mason B, Calame J, Calame S, Sharma S, Mirchandani G, Janks D, Bates J, Noori A, Karnbach A, Lustgarten DL, Sobel BE, Spector P: The temporal variability of dominant frequency and complex fractionated atrial electrograms constrains the validity of sequential mapping in human atrial fibrillation. Heart Rhythm 2010;7:594-595. 21. Jarman JW, Wong T, Kojodjojo P, Spohr H, Davies JE, Roughton M, Francis DP, Kanagaratnam P, Markides V, Davies DW, Peters NS: Spatiotemporal behavior of high dominant frequency during paroxysmal and persistent atrial fibrillation in the human left atrium. Circ Arrhythm Electrophysiol 2012;5:650-658. 22. Gojraty S, Lavi N, Valles E, Kim SJ, Michele J, Gerstenfeld EP: Dominant frequency mapping of atrial fibrillation: Comparison of contact and noncontact approaches. J Cardiovasc Electrophysiol 2009;20:9971004. 23. Schilling RJ, Peters NS, Davies DW: Feasibility of a noncontact catheter for endocardial mapping of human ventricular tachycardia. Circulation 1999;99:2543-2552. 24. Schilling RJ, Kadish AH, Peters NS, Goldberger J, Davies DW: Endocardial mapping of atrial fibrillation in the human right atrium using a non-contact catheter. Eur Heart J 2000;21:550-564. 25. Markides V, Schilling RJ, Ho SY, Chow AW, Davies DW, Peters NS: Characterization of left atrial activation in the intact human heart. Circulation 2003;107:733-739. 26. Oral H, Knight BP, Tada H, Ozaydin M, Chugh A, Hassan S, Scharf C, Lai SW, Greenstein R, Pelosi F Jr, Strickberger SA, Morady F: Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation. Circulation 2002;105:1077-1081. 27. Rostock T, Rotter M, Sanders P, Ja¨ıs P, Hocini M, Takahashi Y, Sacher F, J¨onsson A, O’Neill MD, Hsu LF, Cl´ementy J, Ha¨ıssaguerre M: Fibrillating areas isolated within the left atrium after radiofrequency linear catheter ablation. J Cardiovasc Electrophysiol 2006;17: 807-812. 28. Ha¨ıssaguerre M, Hocini M, Sanders P, Takahashi Y, Rotter M, Sacher F, Rostock T, Hsu LF, Jonsson A, O’Neill MD, Bordachar P, Reuter S, Roudaut R, Cl´ementy J, Ja¨ıs P: Localized sources maintaining atrial fibrillation organized by prior ablation. Circulation 2006;113:616-625. 29. Elvan A, Linnenbank AC, van Bemmel MW, Misier AR, Delnoy PP, Beukema WP, de Bakker JM: Dominant frequency of atrial fibrillation correlates poorly with atrial fibrillation cycle length. Circ Arrhythm Electrophysiol 2009;2:634-644. 30. Ouyang F, Ernst S, Chun J, B¨ansch D, Li Y, Schaumann A, Mavrakis H, Liu X, Deger FT, Schmidt B, Xue Y, Cao J, Hennig D, Huang H, Kuck KH, Antz M: Electrophysiological findings during ablation of persistent atrial fibrillation with electroanatomic mapping and double Lasso catheter technique. Circulation 2005;112:3038-3048. 31. 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. 32. Narayan SM, Shivkumar K, Krummen DE, Miller JM, Rappel WJ: Panoramic electrophysiological mapping but not electrogram morphology identifies stable sources for human atrial fibrillation: Stable atrial fibrillation rotors and focal sources relate poorly to fractionated electrograms. Circ Arrhythm Electrophysiol 2013;6:58-67. 33. 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. 34. Narayan SM, Krummen DE, Clopton P, Shivkumar K, Miller JM: Direct or coincidental elimination of stable rotors or focal sources may explain successful atrial fibrillation ablation: On-treatment analysis of the CONFIRM (CONventional ablation for AF with or without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2013;62:138– 147. 35. Earley MJ, Abrams DJ, Sporton SC, Schilling RJ: Validation of the noncontact mapping system in the left atrium during permanent atrial fibrillation and sinus rhythm. J Am Coll Cardiol 2006;48:485-491.
Organizational Index Mapping to Identify Focal Sources During Persistent Atrial Fibrillation JULIAN W. E. JARMAN, MD(Res.), M.R.C.P,∗ TOM WONG, M.D., F.R.C.P.,∗ PIPIN KOJODJOJO, Ph.D., M.R.C.P.,∗ ,† HILMAR SPOHR, M.Sc., M.B.B.S.,∗ JUSTIN E.R. DAVIES, Ph.D., M.R.C.P.,∗ ,† MICHAEL ROUGHTON, M.Sc.,∗ DARREL P. FRANCIS, M.D., F.R.C.P.,∗ ,† PRAPA KANAGARATNAM, Ph.D., M.R.C.P.,∗ ,† MARK D. O’NEILL, DPHIL, M.R.C.P., F.H.R.S.,∗ VIAS MARKIDES, M.D., F.R.C.P.,∗ D. WYN DAVIES, M.D., F.R.C.P., F.H.R.S.,∗ ,† and NICHOLAS S. PETERS, M.D., F.R.C.P., F.H.R.S.∗ ,† From the ∗ Imperial College London, UK; and †St. Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK
Organizational Index Maps of AF. Introduction: Localized rotors have been implicated in the mechanism of persistent atrial fibrillation (AF). Although regions of highest dominant frequency (DF) on spectral analysis of the left atrium (LA) have been said to identify rotors, other mechanisms such as wavefront collisions will sporadically also generate an inconsistent distribution of high DF. We hypothesized that if drivers of AF were present, their distinctive spectral characteristics would result more from their temporal stability than their high frequency. Methods and Results: Ten patients with persistent AF underwent LA noncontact mapping. Following subtraction of far-field ventricular components, noncontact electrograms at 256 sites underwent fast Fourier transform. Mean absolute difference in DF between 5 sequential 7-second segments of AF was defined as the DF variability (DFV) at each site. Mean ratio of the DF and its harmonics to the total power of the spectrum was defined as the organizational index (OI). Mean DFV was significantly lower in organized areas (OI > 1 SD above mean) than at all sites (0.34 ± 0.04 vs 0.46 ± 0.04 Hz; P < 0.001). When organized areas were ablated during wide-area circumferential ablation, AF organized in remote regions (LA appendage OI ablated vs unablated: +0.21 [0.06–0.41] vs −0.04 [−0.14–0.05]; P = 0.005). Conclusions: At sites of organized activation, the activation frequency was also significantly more stable over time. This observation is consistent with the existence of focal sources, and inconsistent with a purely random activation pattern. Ablation of such regions is technically feasible, and was associated with organization of AF in remote atrial regions. (J Cardiovasc Electrophysiol, Vol. 25, pp. 355-363, April 2014) atrial fibrillation, catheter ablation, dominant frequency, Fourier analysis, rotors, spectral analysis Introduction Modern understanding of persistent atrial fibrillation (AF) has evolved from the multiple reentrant wavelet hypothesis to acknowledge experimental data in animals1-2 and humans,3-5 suggesting fibrillatory conduction away from high-frequency
This work was supported by the British Heart Foundation PG/04/041, RG/10/11/28457, NIHR Biomedical Research Centre funding, and the ElectroCardioMaths Programme of the Imperial BHF Centre of Research Excellence. N.S. Peters, T. Wong, and V. Markides have received research grants from St. Jude Medical. D.W. Davies participated on research grants supported by Medtronic, Boston Scientific, and Rhythmia Medical; reports honoraria from Boston Scientific and Rhythmia Medical; reports serving as a consultant for Medtronic; holds stock options in Rhythmia Medical. Other authors: No disclosures. Address for correspondence: Nicholas S. Peters, M.D., F.R.C.P., F.H.R.S., St. Mary’s Hospital, Praed Street, London, W2 1NY United Kingdom. Fax: +44-20-7886-2291; E-mail: [email protected] Manuscript received 28 July 2013; Revised manuscript received 17 November 2013; Accepted for publication 2 December 2013. doi: 10.1111/jce.12352
localized reentrant circuits, or “‘rotors,” which may represent discrete drivers of AF.6 The rotor hypothesis of persistent AF maintenance provided the theoretical underpinning for recent interest in highfrequency activity as a target for catheter ablation.7-9 Highfrequency atrial activation was considered the hallmark of rotor sites. Targeting of such sites was attempted initially by ablating at the sites of complex fractionated atrial electrograms (CFAEs).7-10 More recently, with the heterogenous nature of CFAE sites becoming apparent, spectral analysis was used to more accurately identify high-frequency activation and high dominant frequency (DF) adopted to target ablation to rotor sites.8,9,11 However, following initial reports of remarkable therapeutic success,7 later randomized trial results of CFAE ablation were disappointing,12-15 while data on high DF ablation outcomes are limited and conflicting.8,9,16,17 DF may inaccurately represent underlying activation rates during AF in epicardial18 and endocardial19 spectral mapping. Spuriously high DF values may be calculated in regions of wavefront collision or turning,19 and thus bystander regions distant from rotors may theoretically show higher DF than a rotor. Additionally, systematic mapping of simultaneous global left atrial DF found DF maps highly spatiotemporally unstable, calling into question their utility for guiding ablation.20,21
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We hypothesized that rotors, or indeed any focal sources, whether reentrant or automatic, need not display the highest DF but, in keeping with other focal and reentrant tachycardias,5 would instead be characterized by the association of a narrow frequency range approximating a single cycle length, referred to as “organization,” and relatively constant frequency DF magnitude in successive time periods, referred to as “temporal stability.” Although transient organization of activation may occur probabilistically, organized regions would not be expected to have greater temporal stability if underlying activation was truly random. To test the hypothesis that organized areas have less variability of DF magnitude over time than the remaining left atrium, and thus may identify focal sources as targets for ablation in persistent human AF, we examined the effects of left atrial ablation on spectral analysis of simultaneous, high-density noncontact (EnSiteArrayTM , St. Jude Medical, St. Paul, MN, USA) endocardial mapping as previously validated in the animal22 and human atrium.21,23,24 Methods Study Patients Consecutive patients referred for first ablation with symptomatic drug-refractory AF that had been persistent for at least 2 years were studied. Antiarrhythmic drugs were stopped at least 5 half-lives preoperatively and no patient was taking amiodarone. The study protocol was approved by the local ethics committee and all procedures were carried out under conscious sedation with written informed consent. Noncontact Mapping A noncontact multielectrode array (EnSite Array; St. Jude Medical) and a 4-mm-tip irrigated ablation catheter (Biosense-Webster, Diamond Bar, CA, USA) were deployed transseptally into the LA, the former anchored by a guidewire in the left superior pulmonary vein. The noncontact system has previously been described in detail.21,23-25 Following detailed left atrial geometry acquisition, persistent AF was recorded with the noncontact system to analyze off-line. Filter settings of noncontact electrograms were 1–150 Hz.16,21 Patients then underwent catheter ablation with the operator blinded to the results of spectral analysis. Subsequently, further noncontact mapping data were collected after all ablation was complete. Noncontact mapping data were subjected to spectral analysis to contrast the characteristics of baseline and postablation persistent AF. Off-Line Signal Processing Noncontact unipolar electrograms sampled at 1,200 Hz were exported from 256 evenly distributed sites on the reconstructed LA surface in temporally sequential 7-second segments.16,21 Off-line analysis used customized software programmed in the MATLAB (Mathworks, Natick, MA, USA) environment with signals processed through the following steps. (1) Subtraction of far-field ventricular components: the averaged far-field ventricular component of the unipolar electrogram at each of the 256 sites was digitally subtracted from the raw signal using a semi-automated algorithm based on a QRS cancellation technique.21 (2) Hanning windowing: the ventricular-subtracted data from each of the
256 points within each 7-second segment were subjected to Hanning windowing to reduce the effect of discontinuity at the extremes of the segment. (3) Fourier transformation: the processed electrograms were then subjected to fast Fourier transform algorithm. Definitions The resultant power frequency spectra in the physiologically relevant 3–20 Hz range at each site were examined using the following definitions. DF: the frequency with highest power on the power frequency spectrum for a 7-second segment. Mean DF: the mean of the 5 DF values identified by analysis of 5 temporally consecutive segments of 7 seconds of AF at a single site. DF variability (DFV): the absolute difference between the DF values in successive pairs of the 5 7-second segments was calculated at each site, and the mean of these 4 values defined the DFV at that site. Organzsational index (OI): the area under the DF peak and its harmonics (within a 0.75 Hz window) in the power frequency spectrum for each 7-second segment at a single site was divided by the total area under the spectrum (Fig. 1)—the mean of the calculated values for the 5 segments was defined as the OI at that site.2 These definitions are illustrated in Figure 2. OI maps and Definition of Organized Areas OI values at 256 sites were plotted on a 3-dimensional virtual LA surface, creating an OI map (Fig. 3). Regions where all OI values were more than 1 standard deviation greater than the mean OI of all sites were defined as organized areas (Fig. 4). Their location was categorized using 12 predefined anatomical areas: 4 pulmonary vein (PV) antra, remaining posterior wall (excluding PV antra), roof, left atrial appendage, base of left atrial appendage, anterior wall, septum, lateral wall and floor. Spatiotemporal Stability: Reproducibility of OI Maps The strength of agreement between OI maps generated utilizing data from 2 successive 35-second time periods prior to ablation was evaluated by calculating the reliability coefficient. This value assesses the proportion of the variance between all OI values in all maps that is attributable to the variation between the OI values at the 256 different sites on individual maps. Thus, a low coefficient indicates that there is a high degree of variance between OI values recorded at individual sites over successive time periods, relative to the degree of variance between the OI values recorded at different sites in a single time period, and thus that the maps are not spatiotemporally stable. Catheter Ablation Using the irrigated 4-mm-tipped catheter, patients underwent wide-area circumferential ablation (WACA) with consistent, anatomically determined linear ablation lesions encircling the left- and right-sided pulmonary veins in pairs. Encircling lesions were joined by a linear roof lesion, and another linear lesion connected the left-sided encircling lesion to the mitral valve annulus. Power was limited to 35 W, and on the posterior wall to 25 W. Subsequently, patients were converted to sinus rhythm with external direct current cardioversion.
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Figure 1. Calculation of organizational index. A band 0.75 Hz either side of the dominant frequency in a power frequency spectrum (top = first). Area under the band is calculated (second). Area under the first harmonic of the dominant frequency is added (third). Resultant area is divided by the total area under the power frequency spectrum (fourth).
Ablation of Organized Areas and Definition of Remote Effect on OI The spatial relationship between organized areas on the baseline OI map and subsequent WACA lesions was examined retrospectively. When highest OI within an organized area was < 1 virtual electrode distance from an ablation line, this organized area was considered ablated (WACAOI group); otherwise, all organized areas were considered un-ablated (WACA-only group). In order to assess the effect of ablation on OI at a site remote from the lesions, the perimeter of the left atrial appendage (LAA) was located with the mapping catheter and labeled during the procedure, and 6 virtual electrodes from within this area were defined as the LAA sample used to examine the impact of ablation on OI in the LAA before and after ablation. Statistical Analysis Normally distributed continuous data were expressed as mean ± standard deviation, and other continuous data as median and range. Comparison between groups uses the paired
or unpaired Student t-test for normally distributed data, or otherwise the Wilcoxon rank sum, Mann–Whitney U, or Fisher’s exact tests. Preferential anatomical distribution of organized areas was assessed with the chi-square test. The correlation was assessed with the Pearson correlation coefficient. The reliability coefficient (R), the true variance as a proportion of the total variance, was used to assess agreement in OI values at multiple locations on a map between 2 time periods. Two-sided P values < 0.05 were considered significant. Results Study Population and Ablation Procedure Ten patients completed the protocol (6 men; age 58 ± 10 years): AF was long-lasting persistent in all patients (median duration 24 months (range 12–56 months)). LA diameter was 47 ± 8 mm and left ventricular ejection fraction 51 ± 10% (Table 1). There was no procedural complication. All patients required external cardioversion from AF to sinus rhythm at the end of the procedure.
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Figure 2. Definitions employed. A stylized drawing of an electrogram at a single left atrial site is used to illustrate how the mean dominant frequency (DF), dominant frequency variability (DFV), and organizational index (OI) at that site are calculated, using the values for DF and OI calculated at 5 sequential 7-second segments of AF.
Characteristics of Organized Areas We found 27 organized areas (median 2, range 2–4, per patient), with median surface area 7 cm2 (range 2–18 cm2 ), representing median 5% (range 1–10%) of total LA surface area. Among all patients at baseline, median lowest OI was 0.17 (range 0.10–0.28) and median highest OI 0.66 (range 0.50–0.75), and median difference between these values 0.44 (range 0.35–0.58). By definition, mean OI in organized areas was higher (0.51 ± 0.02) than mean OI of all 256 sites (0.41 ± 0.02). Organized areas were frequently located at the PV antra (44%, P = 0.32 compared with non-PV areas) (Fig. 5). Median reliability coefficient between successive 35-second OI maps was 0.47 (range 0.29–0.70), indicating moderate agreement between maps (Fig. 6).
Relationship Between Organization and Temporal Stability Dominant frequency variability (DFV) in organized areas was lower than DFV among all LA sites in every patient and for the whole group (0.34 ± 0.04 vs 0.46 ± 0.04 Hz; P < 0.001), indicating significantly greater temporal stability of DF in these areas, and consistent with our hypothesis. Relationship Between Organization and Dominant Frequency Among all patients, mean DF among sites in organized areas (6.31 ± 0.18 Hz) was modestly but significantly higher than among all LA sites (6.21 ± 0.17 Hz; P = 0.003).
Figure 3. Organizational index map. In a right superior view, OI values are plotted alongside virtual electrodes colored according to a normalized scale with interpolation between electrodes. Seven-second ventricular-subtracted noncontact electrograms are displayed on left. Their power frequency spectra are displayed underneath with 3 – 15 Hz range on the horizontal axis. Values for OI, mean DF, and DFV (calculated from 35 seconds of data) displayed below. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
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Figure 4. Map of organized areas. The same map as Figure 3, with color bar set to only color areas where OI is >1 standard deviation above the mean. A single organized area is seen on the left atrial roof. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
TABLE 1 Patient Characteristics
Male sex Age at time of study (years) LA size (mm) LVEF (%) Time in persistent AF (months)
values compared to other LA sites (mean LA OI 0.43 [range 0.33–0.58], highest LA OI 0.66 [range 0.51–0.79]), whereas following ablation, due to a rise in overall LA OI, their OI was close to the LA mean (mean LA OI 0.54 [0.37–0.85], highest LA OI 0.79 [range 0.6–0.95]).
All Patients
WACA-OI WACA-Only Group Group P Value
4/10 58 ± 10
2/6 62 (42–71)
4/4 57 (47–67)
0.071 0.762
Location of Data Samples and Validation of EnSite System During Atrial Tachycardia
47 ± 8 45 (41–50) 51 ± 10 54 (39–65) 24 (12–56) 22 (12–32)
47 (43–67) 51 (31–54) 24 (19–56)
0.476 0.352 0.610
Data points among all patients were 29.6 ± 9.8 mm from the center of the array, with 85% of all points located < 40 mm from the center. In 1 WACA-OI patient, AF converted to atrial tachycardia (AT) during WACA, before subsequently degenerating again to highly organized AF. This provided a useful opportunity to validate the EnSite system as used in our protocol. Contact electrograms revealed a stable cycle length of 222 milliseconds during AT. Noncontact data during AT were used to create a DF map following subtraction of the far-field ventricular components (Fig. 8). Two hundred fortysix of 256 sites (96%) show DF 4.5 Hz, confirming correct interpretation of the underlying atrial cycle length. At the remaining 10 sites, DF was 9.1 Hz: these sites on the posterior wall overlay ablation lesions encircling the pulmonary veins and the DF values calculated reflected double counting of the underlying atrial activation rate at these lines of block.
AF = atrial fibrillation; LA = left atrial; LVEF = left ventricular ejection fraction. Data are presented as mean ± standard deviation, or median (range). P values are for differences between WACA-OI and WACA-only groups.
However, there was no overall correlation between mean DF and OI (mean correlation coefficient 0.17 ± 0.06). OI Ablation and Impact on Remote Regions Among 10 patients undergoing WACA, 6 had ablation of organized areas (WACA-OI group) and 4 did not (WACAonly group). There were no significant differences between the patient characteristics of the 2 groups (Table 1). Only in the WACA-OI group was there an increase in OI in the LAA, and therefore spatially remote from the ablation; WACA-OI group (0.21 [range 0.06–0.41]) compared with the WACAonly group (−0.04 [range −0.15–0.05]; P = 0.005) (Fig. 7). The OI in sites adjacent to where highest OI was ablated in the WACA-OI group did not change significantly (from 0.55 [range 0.34–0.74] to 0.54 [0.28–0.89]; [P = 0.911]). However, prior to ablation, these sites had relatively high OI
Discussion The principle finding of this study was that, consistent with our hypothesis regarding the expected spectral characteristics of focal sources, including localized reentrant
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Figure 5. Regional distribution of organized areas. Left atrial geometry displayed in posteroanterior (left) and anteroposterior (right) projections. LAA = left atrial appendage; LIPV = left interior pulmonary vein; LSPV = left superior pulmonary vein; PV = pulmonary vein; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
Figure 6. Temporally sequential 35-second organizational index maps. Right anterior oblique cranial projection. OI values are plotted alongside virtual electrodes and organized areas (OI > 1 standard deviation above the mean) are colored using normalized scales. Organized areas remain in relatively stable locations. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
“rotors,” driving persistent AF, areas of organized activation were associated with significantly greater temporal stability of DF than in other areas. This previously unreported finding, of areas that are both organized and spatiotemporally stable, would not be expected with a purely randomly distributed underlying activation pattern and is consistent with the presence of focal sources driving AF in these patients. Additionally, where ablation fortuitously occurred in organized areas, this was associated with greater organization of AF in remote regions, consistent with elimination of focal sources. Following ablation in organized areas, the degree of organization of adjacent sites returned to the average for the atrium overall.
Spectral Mapping of AF With the realization that pulmonary vein isolation alone is usually an ineffective treatment for persistent AF,26 recent investigation has focused on identifying (ideally discrete) targets to guide additional left atrial substrate modification. Evidence of the existence of high-frequency sources, which may maintain AF,1-5,27,28 including data from endocardial contact mapping27,28 and data suggesting a reentrant mechanism in humans,4 naturally suggested these phenomena as possible targets. The presence of activation frequency gradients from the drivers to surrounding atrial tissue informed the
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Figure 7. Organizational index (OI) maps with and without OI ablation. Patient A has highest OI anterior to the right superior pulmonary vein at baseline (A1). The region is transected by WACA (black line). After all ablation (A2), mean appendage OI has increased to 0.86. Patient B has highest OI on the anterior wall at baseline (B1). WACA lesions do not encroach on this area. After all ablation (B2) over an hour later, highest OI remains present and mean appendage OI has reduced to 0.35. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
development of spectral mapping to systematically identify areas with high DF, predicated on the assumption that DF would proxy underlying activation rates. However, the efficacy of prospective targeting of such sites during AF has yet to be proven.
Limitations of DF Mapping DF can sometimes misrepresent underlying activation rates during AF in both epicardial18 and endocardial19,29 studies. This can occur when an electrogram’s amplitude and rate vary simultaneously, or through “double counting” at points where wavefronts collide or turn. All of these are characteristically widespread and common phenomena in AF and would be consistent with the observation that sites of high or “highest” DF values are spatiotemporally unstable,20,21 and the absence of convincing data showing a beneficial effect of targeting sites of high DF in patients with persistent AF. In 1 nonrandomized trial where DF ablation was prospectively applied in 18 patients with persistent AF,8 all patients underwent additional circumferential pulmonary vein isolation (PVI), yet only 50% maintained sinus rhythm after 8 months, a result comparable with outcomes seen when circumferential PVI has been used alone in other studies.30 When DF ablation was combined with PVI in another trial the results were not better than in a control group undergoing PVI alone.17
Organizational Index Mapping For these reasons we hypothesized that highest DF was not a necessary spectral characteristic of a focal source driving persistent AF. We further hypothesized that, in keeping with the spectral characteristics of other focal or reentrant tachycardias,5 they would principally be characterized by the association of organized activation (a narrow frequency range) with relative temporal stability of their DF (relatively consistent frequency magnitude). This combination of characteristics, which have formed part of the definition of rotors in previous studies,2,3,5 would not be expected if created by continuously varying bystander sites of wavefront collision. The central finding of this study, that low DF variability is systematically associated with areas of high OI, has not previously been reported and is consistent with the existence of focal sources during persistent AF. It would not be expected with a randomly determined activation pattern. The finding that OI maps, unlike DF maps, have moderate reproducibility between 35 second periods is more consistent with the properties expected of stable drivers. Unlike DF maps that lack spatiotemporal stability (Kappa values −0.07–0.22),20,21 OI maps have moderate reproducibility (median Kappa 0.47) and thus may have greater utility to guide ablation to particular regions of the atria, although accuracy, at least using the techniques in this study, is still limited. Thus, although the findings of the present study support the concept that fixed regions of high organizational index
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Figure 8. Mean dominant frequency map of atrial tachycardia. Mean DF values are shown at each site and color coded to a normalized scale without interpolation between points. A single value of 4.5 Hz, corresponding exactly to tachycardia cycle length 222 milliseconds, is seen at all sites, with the exception of 10 sites where 9.1 Hz is shown: these reflect double counting over ablation lesions posterior to the RIPV and LSPV. LAO = left anterior oblique projection; LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein; MVA = mitral valve annulus; PA = posteroanterior projection; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein. For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
identify sites of stable focal sources during AF, this study does not prove the existence of rotors and other possible explanations include localized bystander channels of regular activation determined by local refractory periods. We found that ablation incorporating sites of high OI was associated with increasing organization of the left atrial appendage, a region spared from direct ablation, in all patients. This was not observed in patients in whom OI was not ablated during WACA. If OI ablation reduces the number of active focal sources, it would be consistent with activation in a remote region becoming incrementally more organized; however, in this small number of patients, this finding should be interpreted with caution. Recently, reentrant sources have been convincingly identified in human atria by applying an alternative spectral analysis technique, the Hilbert transform, combined with wave similarity analysis, to high-density contact mapping data.31-33 The mean rotor cycle length observed in persistent AF was 163 milliseconds, equivalent to 6.1 Hz and similar to the mean DF of 6.3 Hz in our study.31 There was no correlation between the location of focal sources and that of highfrequency CFAEs.32 Focal ablation at these sites sometimes terminated AF and appeared to improve the success of widearea circumferential pulmonary vein isolation,33 even when performed unintentionally.34 Limitations There are many questions that could not be answered in a study of this design. These include the lack of contact data, right atrial activation data, and how changes in autonomic tone may have affected OI maps. Additionally, low OI values might theoretically be seen in regions distant from the center of the multielectrode array due to lower signal-tonoise ratio. In this study 15% of data samples were >40 mm from the array center, beyond which data quality may deteriorate;35 however, organized areas were found in almost
all atrial areas, commonly including the pulmonary vein ostia and left atrial appendage, which may be in relatively polar positions relative to the array. Finally, the definition of organized areas employed (OI > 1 SD above the mean OI) made it inevitable that organized areas would be described in all patients—therefore, the relationship between organization and lower DF variability described cannot provide evidence of the frequency with which true rotors or focal sources are found among a group of patients. Conclusions Simultaneous spectral mapping throughout the human left atrium during persistent AF reveals that regions of organized activation have greater temporal stability of their DF than other areas, and also exhibit considerable spatiotemporal stability. This finding is consistent with the existence of focal sources during persistent AF. Ablation of such areas guided by noncontact mapping technology is technically feasible and when ablated in this study, was associated with the organization of AF in remote atrial regions. References 1. 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. 2. Kalifa J, Tanaka K, Zaitsev AV, Warren M, Vaidyanathan R, Auerbach D, Pandit S, Vikstrom KL, Ploutz-Snyder R, Talkachou A, Atienza F, Guiraudon G, Jalife J, Berenfeld O: Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation 2006;113:626-633. 3. Sahadevan J, Ryu K, Peltz L, Khrestian CM, Stewart RW, Markowitz AH, Waldo AL: Epicardial mapping of chronic atrial fibrillation in patients: Preliminary observations. Circulation 2004;110:3293-3299. 4. Atienza F, Almendral J, Moreno J, Vaidyanathan R, Talkachou A, Kalifa J, Arenal A, Villacast´ın JP, Torrecilla EG, S´anchez A, PloutzSnyder R, Jalife J, Berenfeld O: Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: Evidence for a reentrant mechanism. Circulation 2006;114:2434-2442.
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