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Stability of Rotors and Focal Sources for Human Atrial Fibrillation: Focal Impulse and Rotor Mapping (FIRM) of AF Sources and Fibrillatory Conduction VIJAY SWARUP, M.D.,∗ TINA BAYKANER, M.D., M.P.H.,† ARMAND ROSTAMIAN, M.D.,† JAMES P. DAUBERT, M.D.,§ JOHN HUMMEL, M.D.,¶ DAVID E. KRUMMEN, M.D.,† RISHI TRIKHA, B.S.,† JOHN M. MILLER, M.D.,∗∗ GERY F. TOMASSONI, M.D.,†† and SANJIV M. NARAYAN, M.D., Ph.D.‡‡ From the ∗ Arizona Heart Hospital, Phoenix, Arizona; †University of California and Veterans Affairs Medical Centers, San Diego, California; §Duke University, Durham, North Carolina; ¶Ohio State University, Columbus, Ohio; ∗∗ Indiana University, Indianapolis, Indiana; ††Central Baptist Hospital, Lexington, Kentucky; and ‡‡Stanford University, Palo Alto, California, USA
Stable Human AF Rotors. Introduction: Several groups report electrical rotors or focal sources that sustain atrial fibrillation (AF) after it has been triggered. However, it is difficult to separate stable from unstable activity in prior studies that examined only seconds of AF. We applied phase-based focal impulse and rotor mapping (FIRM) to study the dynamics of rotors/sources in human AF over prolonged periods of time. Methods: We prospectively mapped AF in 260 patients (169 persistent, 61 ± 12 years) at 6 centers in the FIRM registry, using baskets with 64 contact electrodes per atrium. AF was phase mapped (RhythmView, Topera, Menlo Park, CA, USA). AF propagation movies were interpreted by each operator to assess the source stability/dynamics over tens of minutes before ablation. Results: Sources were identified in 258 of 260 of patients (99%), for 2.8 ± 1.4 sources/patient (1.8 ± 1.1 in left, 1.1 ± 0.8 in right atria). While AF sources precessed in stable regions, emanating activity including spiral waves varied from collision/fusion (fibrillatory conduction). Each source lay in stable atrial regions for 4,196 ± 6,360 cycles, with no differences between paroxysmal versus persistent AF (4,290 ± 5,847 vs. 4,150 ± 6,604; P = 0.78), or right versus left atrial sources (P = 0.26). Conclusions: Rotors and focal sources for human AF mapped by FIRM over prolonged time periods precess (“wobble”) but remain within stable regions for thousands of cycles. Conversely, emanating activity such as spiral waves disorganize and collide with the fibrillatory milieu, explaining difficulties in using activation mapping or signal processing analyses at fixed electrodes to detect AF rotors. These results provide a rationale for targeted ablation at AF sources rather than fibrillatory spiral waves. (J Cardiovasc Electrophysiol, Vol. 25, pp. 1284-1292, December 2014) atrial fibrillation, catheter ablation, FIRM mapping, focal impulse, rotors
This manuscript was processed by a guest editor. It was presented by Dr. Swarup at the AF Summit of the 34th Annual Sessions of the Heart Rhythm Society in Denver, Colorado May 2013 and published in abstract form. Dr. Swarup has received consulting fees/honoraria from Biosense Webster and research grants from Biosense Webster, Medtronic, Boston Scientific, St. Jude Medical, and Biotronik. Dr. Krummen has received consulting fees from Insilicomed and research grants from the American Heart Association and NIH. He has also received fellowship support from Medtronic, St. Jude Medical, Biosense Webster, Boston Scientific, and Biotronik. Dr. Daubert has received consulting fees/honoraria from Medtronic, St. Jude Medical, Boston Scientific, Sorin Group, and CardioFocus. He has received research grants from Boston Scientific, Biosense Webster, Medtronic, and Gilead Sciences. He has also received fellowship support from Medtronic, Boston Scientific, Biotronik, St. Jude Medical, Biosense Webster, and Bard Electrophysiology. Dr. Hummel reports consulting fees/honoraria from Medtronic and research grants from St. Jude Medical and Boston Scientific. Dr. Miller reports consulting fees/honoraria from Biosense Webster, Biotronik, and Medtronic and fellowship support from Medtronic, Boston Scientific, Biotronik, and Biosense Webster.
Dr. Tomassoni reports consulting fees/honoraria from Topera, Stereotaxis, Biosense Webster, St. Jude Medical, Boston Scientific, Pfizer, and Atricure. He also serves as CMO of Stereotaxis. Dr. Narayan was supported by NIH (HL83359, HL103800). Dr. Narayan is coauthor of intellectual property owned by the University of California Regents and licensed to Topera Inc. Topera does not sponsor any research, including that presented here. Dr. Narayan holds equity in Topera, and reports having received honoraria from Medtronic, St. Jude Medical, Biotronik, and Boston Scientific. He has received consulting fees from the American College of Cardiology Foundation and Topera and royalty income from UpToDate. His Institution has received fellowship support from Medtronic, St. Jude Medical, Biosense Webster, Boston Scientific, and Biotronik. Dr. Baykaner has no disclosures. Address for correspondence: Vijay Swarup, M.D., Director Cardiac Electrophysiology, Arizona Heart Rhythm Center, Phoenix, AZ, USA. E-mail: [email protected] Manuscript received 27 March 2014; Revised manuscript received 12 September 2014; Accepted for publication 19 September 2014. doi: 10.1111/jce.12559
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Introduction Despite advances in anatomical imaging and energy delivery, ablation for atrial fibrillation (AF) is suboptimal.1 Ablation has mostly focused on triggers in the pulmonary veins (PV), but there is renewed interest in substrates that sustain AF after it is triggered. Electrophysiological substrates likely include conduction slowing2-5 or repolarization abnormalities,6-10 which may show patient-specific distributions4,5,8,9 and may reflect structural fibrosis and scar.11,12 Alterations in atrial electrophysiology may in turn create rotors or focal sources for human AF that we13,14 and others15-17 have recently reported. A central question is whether rotors are stable and should be amenable to limited ablation, or unstable and require widespread “debulking.” We hypothesized that rotors sustaining human AF are stable, i.e., lie in localized regions over time, rather than diffuse. This is consistent with the localized source model for AF, described by Mines and more recently Jalife et al.18 The localized source model explains diverse observations, including the need for wide ablation if source locations are not known a priori, but also modulation of AF by a few lesions,19 incomplete linear or wide-area lesions before PV isolation is achieved20 if they pass a source. The localized source model is also consistent with stable regions of high rate21-23 and lower surrounding rates,22,24 and stable vectors25 over time. Many of these observations are difficult to explain by meandering mechanisms.26 Spatial stability of AF sources is central to whether their ablation should be localized or widespread. Rotors driving human AF were undetected18,26,27 until recently,13 partly due to small analyzed areas26 and the limitations of activation mapping including difficulties in defining local activation in AF,9 small electrode grids that may miss precessing (limited migration of) rotational activity (“wobbles”),28,29 and disorganization of spiral arms emanating from a rotor via “fibrillatory conduction”.18 Focal impulse and rotor modulation (FIRM) uses phase algorithms to track human AF rotors precessing in 2–3 cm2 areas30 whose ablation has been shown by many groups to produce higher long-term freedom from AF than conventional ablation.13,14 It is unclear whether recent reports of rotor instability by other methods15,31 are limited by these factors, or whether recording AF for short periods of seconds may miss stability evident over minutes or longer. We set out to quantify the stability of rotor and focal sources for human AF over prolonged periods to time and
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TABLE 1 Clinical Characteristics of Patients Paroxysmal Persistent AF
Characteristic All patients Age in years, mean (SD) Gender (male/female) Left atrial diameter (mm), mean (SD) LVEF (%), mean (SD) Prior unsuccessful AF ablation Previously failed amiodarone
91 60.5 (11) 74/17 46.7 (9) 59(12) 24.0% (22/91) 16.7% (16/91)
169 62 (11) 147/22 52 (10) 52 (13) 41.2% (72/169) 32.8% (55/169)
P
0.313 0.223 60 days after discontinuing amiodarone (Table 1). Via femoral venous access, a multipolar catheter was placed in the coronary sinus
Figure 1. Panoramic contact mapping of right and left atria for FIRM-guided mapping of AF sources. A: Good right atrial coverage, with conformation of splines to the atrial contour indicating good contact, with one spline near the tricuspid annulus. B: Good left atrial coverage, except for the septum and dilated right pulmonary vein antra in this case (indicated by contour of ablation catheter). Areas of poor electrode contact are represented as continuously black regions on FIRM maps. 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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and a 64 pole basket catheter (Constellation, Boston Scientific Corp., Natick, MA, USA) was advanced sequentially to right then left atria via 8.5F sheaths (Fig. 1) to optimize atrial contact using fluoroscopy, electrography, and/or intracardiac echocardiography. Care was taken to position the right atrial basket in patients with right atrial permanent pacemaker leads.13 Patients presenting in sinus rhythm were paced into AF as described,32 adding isoproterenol if required to induce sustained AF, in which case it was maintained throughout the case. Unipolar signals from the multipolar catheter were filtered at 0.05–500 Hz for digital export from electrophysiological recorders at each site (Bard Pro, Billerica, MA, USA; Cardiolab, GE Medical, Milwaukee, WI, USA). AF Mapping Three-dimensional activation information from the basket (Supplemental figure shows coverage of the vast majority of the atria) was analyzed using a FDA-approved system (RhythmViewTM , Topera Inc., Menlo Park, CA, USA) that uses described algorithms32,33 to map an activation trail of propagation in AF using the rate-response of repolarization,6-10 conduction,4,7 cycle length,9,34 and phase analysis to filter physiological signal from noise. AF was analyzed in multiple 1-minute “epochs” to produce videos (FIRM maps) that were projected onto a grid. We assessed the stability of rotors/sources in multiple recordings over several minutes prior to FIRM-guided ablation.
FIRM-guided or conventional ablation. In FIRM-guided patients, radiofrequency energy was delivered to the region of rotation or focal origin, for ࣈ5–10 minutes per source repeated for all sources, followed by conventional ablation. Conventional ablation1 comprised PV isolation verified using a circular catheter (LassoTM , Biosense Webster, Diamond Bar, CA, USA or Optima, St. Jude Medical, Minnetonka, MN, USA) and linear lesions at the left atrial roof in patients with persistent AF. Other clinically indicated ablation, e.g., of atrial flutter, was performed at the discretion of the operator at each site. Statistical Analysis Continuous data are represented as mean ± standard deviation. The Student’s t-test was used to compare continuous variables between 2 groups, such as the number of rotor cycles. Paired continuous variables were compared using linear regression and the paired t-test. The chi-square test was applied to contingency tables for categorical variables. A P value of 28,421 cycles (=90 × 60,000/190) during mapping. Figure 3 presents a stable left atrial AF rotor with fibrillatory interference of its spiral arms, in a 58-year-old man with paroxysmal AF and no prior ablation. The rotor precessed in a stable region of the mid-posterior left atrium for
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Figure 2. Stable AF rotor with consistent spiral arms. This AF was in a 47-year-old gentleman with persistent AF despite extensive left atrial ablation. A dominant rotor was found in the right atrium (shown) that produced a clockwise emanating spiral wave for over 90 minutes of mapping (>28,421 cycles). Fibrillatory breakdown from the rotor affected only the periphery of the spiral arms (panel A). This rotor was temporospatially stable until eliminated by FIRM-guided ablation. TABLE 2 AF Source Dynamics Characteristics
Paroxysmal
Persistent AF
P
Number of patients FIRM-mapped AF cycle length (coronary sinus), milliseconds
91 194 ± 29 All patients 100% (91/91) 2.7 ± 1.4 1.8 ± 1.1 1.0 ± 0.8
169 183 ± 29
0.005
98.8% (167/169) 2.9 ± 1.4 1.8 ± 1.1 1.2 ± 0.9
4,290 ± 5,847
4,150 ± 6,604
0.543 0.283 0.930 0.083 0.781
4,114 ± 5,836
3,940 ± 7,458
4,681 ± 5,890 Patients with no prior ablation 100% (69/69) 2.7 ± 1.4 1.8 ± 1.1 1.0 ± 0.8
4,509 ± 4,803
4,538 ± 6,372
3,631 ± 5,230
4,304 ± 6,353
3,338 ± 5,499
5,100 ± 6,444
4,162 ± 4,681
No. of patients with detected sources No. of concurrent AF sources No. of LA sources No. of RA sources All sources: no. of cycles mapped Mean ± SD Left atrial sources, no. of cycles mapped Mean ± SD Right atrial sources, no. of cycles mapped Mean ± SD No. of patients with detected sources No. of concurrent AF sources No of LA sources No of RA sources All cycles, no. of cycles mapped Mean ± SD Left atrial sources, no. of cycles mapped Mean ± SD Right atrial sources, no. of cycles mapped Mean ± SD
Percentages are for each population (column-wise). All patients had biatrial mapping.
99% (96/97) 2.9 ± 1.4 1.8 ± 1.1 1.2 ± 0.9
0.795 0.808
1.000 0.283 0.823 0.08 0.094 0.152 0.300
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Figure 3. Stable, spatially precessing rotor (counterclockwise) with varying spiral waves from interaction with fibrillatory activity in a 58-year-old gentleman with paroxysmal AF, left atrial diameter of 60 mm, LVEF 60% and no prior ablation. FIRM mapping revealed a rotor core in the mid-posterior left atrium for > 30 minutes (10,227 cycles). Despite stability of the rotor, the emanating counterclockwise spiral wave (arrows) in both panels showed variable organization due to dynamic cycle-to-cycle interaction with fibrillatory wavelets (lines with block). This rotor was temporospatially stable until eliminated by FIRM-guided ablation. TABLE 3 Regional Distribution of FIRM-Mapped AF Sources Location Left atrium Left atrial roof Anterior left atrium Posterior/inferior left atrium Near left pulmonary veins Near right pulmonary veins Right atrium Lateral Posterior Septal
Paroxysmal (n = 240)
Persistent AF (n = 482)
P
167 (70%) 38 (16%) 32 (13%) 46 (19%) 35 (15%) 16 (7%) 73 (30%) 32 (13%) 27 (11%) 14 (6%)
305 (63%) 72 (15%) 47 (10%) 87 (18%) 61 (13%) 38 (8%) 177 (37%) 87 (18%) 37 (8%) 53 (11%)
0.093 0.778 0.155 0.744 0.492 0.544 0.093 0.100 0.118 0.023
>30 minutes (=30 × 60,000/176 = 10,227 cycles), with spiral arms that disorganized (arrows) via collision from a (separately identified) right atrial rotor and transient rotational spins (“fibrillatory conduction”). Figure 4 presents a rotor in AF induced by pacing; after >45 minutes the AF self-terminated then spontaneously reinitiated in a stable location as indicated.
Source Stability and Regionality AF sources precessed within spatially reproducible regions for all patients during mapping for 4,196 ± 6,360 cycles (Table 2; Figs. 2-5) over tens of minutes. There were no differences in source stability between paroxysmal and persistent AF.
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Figure 4. Stability of left atrial rotor in spontaneous versus induced AF. A: FIRM maps of both atria show a left atrial rotor in pacing-induced AF, producing counterclockwise spiral waves (white arrow) in AF. AF terminated and spontaneously reinitiated. Forty-five minutes later, B: FIRM maps show this left atrial rotor in the same region producing a counterclockwise spiral wave. This FIRM map also illustrates transient circular activity in the right atrium (dashed arrow) that was not consistent over time and not diagnosed as a rotor on FIRM mapping. The left atrial rotor was spatiotemporally stable for > 45 minutes (>14,210 cycles) until eliminated by FIRM-guided ablation.
The Supplemental online movie shows a left atrial AF rotor in a 59-year-old man with persistent AF, showing spatial stability for >200 cycles with varying peripheral breakdown. The actual rotor core precesses within the area indicated by the arrows in the mid-posterior left atrial wall, causing slight variations in the rotational path but substantial variation in the peripheral transient rotational spins. This rotor was actually stable for tens of minutes (>3,000 cycles) until ablated in this location outside a typical wide-area PVI lesion set. As shown in Table 3, stable sources lay in multiple biatrial locations near and remote from the PV in patients with paroxysmal as well as persistent AF. Discussion This is the first study to quantify the spatiotemporal dynamics of human AF over prolonged periods of time in terms of rotors, focal sources, and fibrillatory conduction. In this prospective multicenter registry of FIRM, the largest series to date, AF rotors and focal sources were not as “fixed” as atrial tachycardias but precessed for tens of minutes in spatially reproducible areas, i.e., were temporospatially stable. Conversely, emanating activity was variable and fused with fibrillatory conduction. On phase analysis, AF source stability was similar for left versus right atria, for paroxysmal versus persistent AF, and for patients with no prior ablation versus AF despite prior ablation. Rotor stability explains the effectiveness of localized targeted ablation now shown by several groups, while precession and the complex dynamics of fibrillatory conduction may explain differences in the detection or stability of rotors using different techniques. Stable Sources and Fibrillatory Conduction in Human AF This prospective multicenter study further supports localized sources as primary maintaining mechanisms for human AF, as proposed by Mines et al. and Sir Thomas Lewis, then shown in animal models showing spiral waves (rotors).18 There are now several reports on the FIRM of rotors and fo-
cal sources,14,17,35,37 and other groups have shown evidence for human AF rotors using other techniques.15,16,31 Mechanistically, these results demonstrate in a large population that human AF is characterized by organized rotors whose spiral arms disorganize into fibrillatory conduction.18 Therefore, unlike macroreentry around an obstacle, spiral arms are less suitable targets for bisecting linear lesions, although such lesions may still be effective if they are close enough to the rotor core to reduce the elbow room for rotation around the core.38 Studies are needed to define if AF rotor precession is constrained by electrical,27 neural,39 or structural11,12 remodeling, and to define the mechanisms causing fibrillatory conduction. Conversely, in the multiwavelet hypothesis, disorganized waves generate AF without preferred regions or AF driving sources. However, that hypothesis cannot readily explain results from localized, limited ablation. Notably, epicardial mapping showing disorganized activity without sources26 has not mapped wide atrial areas simultaneously, necessary to identify precessing AF sources without the ability to “register” maps from different regions mapped at different time points, but examined areas (60/64 displayed channels. (Bard Pro, Natick, MA); (B) 55/56 displayed channels out of 64 recorded (on Carto, Biosense-Webster, Diamond Bar, CA). Video S2.
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Stability of Rotors and Focal Sources for Human Atrial Fibrillation: Focal Impulse and Rotor Mapping (FIRM) of AF Sources and Fibrillatory Conduction VIJAY SWARUP, M.D.,∗ TINA BAYKANER, M.D., M.P.H.,† ARMAND ROSTAMIAN, M.D.,† JAMES P. DAUBERT, M.D.,§ JOHN HUMMEL, M.D.,¶ DAVID E. KRUMMEN, M.D.,† RISHI TRIKHA, B.S.,† JOHN M. MILLER, M.D.,∗∗ GERY F. TOMASSONI, M.D.,†† and SANJIV M. NARAYAN, M.D., Ph.D.‡‡ From the ∗ Arizona Heart Hospital, Phoenix, Arizona; †University of California and Veterans Affairs Medical Centers, San Diego, California; §Duke University, Durham, North Carolina; ¶Ohio State University, Columbus, Ohio; ∗∗ Indiana University, Indianapolis, Indiana; ††Central Baptist Hospital, Lexington, Kentucky; and ‡‡Stanford University, Palo Alto, California, USA
Stable Human AF Rotors. Introduction: Several groups report electrical rotors or focal sources that sustain atrial fibrillation (AF) after it has been triggered. However, it is difficult to separate stable from unstable activity in prior studies that examined only seconds of AF. We applied phase-based focal impulse and rotor mapping (FIRM) to study the dynamics of rotors/sources in human AF over prolonged periods of time. Methods: We prospectively mapped AF in 260 patients (169 persistent, 61 ± 12 years) at 6 centers in the FIRM registry, using baskets with 64 contact electrodes per atrium. AF was phase mapped (RhythmView, Topera, Menlo Park, CA, USA). AF propagation movies were interpreted by each operator to assess the source stability/dynamics over tens of minutes before ablation. Results: Sources were identified in 258 of 260 of patients (99%), for 2.8 ± 1.4 sources/patient (1.8 ± 1.1 in left, 1.1 ± 0.8 in right atria). While AF sources precessed in stable regions, emanating activity including spiral waves varied from collision/fusion (fibrillatory conduction). Each source lay in stable atrial regions for 4,196 ± 6,360 cycles, with no differences between paroxysmal versus persistent AF (4,290 ± 5,847 vs. 4,150 ± 6,604; P = 0.78), or right versus left atrial sources (P = 0.26). Conclusions: Rotors and focal sources for human AF mapped by FIRM over prolonged time periods precess (“wobble”) but remain within stable regions for thousands of cycles. Conversely, emanating activity such as spiral waves disorganize and collide with the fibrillatory milieu, explaining difficulties in using activation mapping or signal processing analyses at fixed electrodes to detect AF rotors. These results provide a rationale for targeted ablation at AF sources rather than fibrillatory spiral waves. (J Cardiovasc Electrophysiol, Vol. 25, pp. 1284-1292, December 2014) atrial fibrillation, catheter ablation, FIRM mapping, focal impulse, rotors
This manuscript was processed by a guest editor. It was presented by Dr. Swarup at the AF Summit of the 34th Annual Sessions of the Heart Rhythm Society in Denver, Colorado May 2013 and published in abstract form. Dr. Swarup has received consulting fees/honoraria from Biosense Webster and research grants from Biosense Webster, Medtronic, Boston Scientific, St. Jude Medical, and Biotronik. Dr. Krummen has received consulting fees from Insilicomed and research grants from the American Heart Association and NIH. He has also received fellowship support from Medtronic, St. Jude Medical, Biosense Webster, Boston Scientific, and Biotronik. Dr. Daubert has received consulting fees/honoraria from Medtronic, St. Jude Medical, Boston Scientific, Sorin Group, and CardioFocus. He has received research grants from Boston Scientific, Biosense Webster, Medtronic, and Gilead Sciences. He has also received fellowship support from Medtronic, Boston Scientific, Biotronik, St. Jude Medical, Biosense Webster, and Bard Electrophysiology. Dr. Hummel reports consulting fees/honoraria from Medtronic and research grants from St. Jude Medical and Boston Scientific. Dr. Miller reports consulting fees/honoraria from Biosense Webster, Biotronik, and Medtronic and fellowship support from Medtronic, Boston Scientific, Biotronik, and Biosense Webster.
Dr. Tomassoni reports consulting fees/honoraria from Topera, Stereotaxis, Biosense Webster, St. Jude Medical, Boston Scientific, Pfizer, and Atricure. He also serves as CMO of Stereotaxis. Dr. Narayan was supported by NIH (HL83359, HL103800). Dr. Narayan is coauthor of intellectual property owned by the University of California Regents and licensed to Topera Inc. Topera does not sponsor any research, including that presented here. Dr. Narayan holds equity in Topera, and reports having received honoraria from Medtronic, St. Jude Medical, Biotronik, and Boston Scientific. He has received consulting fees from the American College of Cardiology Foundation and Topera and royalty income from UpToDate. His Institution has received fellowship support from Medtronic, St. Jude Medical, Biosense Webster, Boston Scientific, and Biotronik. Dr. Baykaner has no disclosures. Address for correspondence: Vijay Swarup, M.D., Director Cardiac Electrophysiology, Arizona Heart Rhythm Center, Phoenix, AZ, USA. E-mail: [email protected] Manuscript received 27 March 2014; Revised manuscript received 12 September 2014; Accepted for publication 19 September 2014. doi: 10.1111/jce.12559
Swarup et al.
Introduction Despite advances in anatomical imaging and energy delivery, ablation for atrial fibrillation (AF) is suboptimal.1 Ablation has mostly focused on triggers in the pulmonary veins (PV), but there is renewed interest in substrates that sustain AF after it is triggered. Electrophysiological substrates likely include conduction slowing2-5 or repolarization abnormalities,6-10 which may show patient-specific distributions4,5,8,9 and may reflect structural fibrosis and scar.11,12 Alterations in atrial electrophysiology may in turn create rotors or focal sources for human AF that we13,14 and others15-17 have recently reported. A central question is whether rotors are stable and should be amenable to limited ablation, or unstable and require widespread “debulking.” We hypothesized that rotors sustaining human AF are stable, i.e., lie in localized regions over time, rather than diffuse. This is consistent with the localized source model for AF, described by Mines and more recently Jalife et al.18 The localized source model explains diverse observations, including the need for wide ablation if source locations are not known a priori, but also modulation of AF by a few lesions,19 incomplete linear or wide-area lesions before PV isolation is achieved20 if they pass a source. The localized source model is also consistent with stable regions of high rate21-23 and lower surrounding rates,22,24 and stable vectors25 over time. Many of these observations are difficult to explain by meandering mechanisms.26 Spatial stability of AF sources is central to whether their ablation should be localized or widespread. Rotors driving human AF were undetected18,26,27 until recently,13 partly due to small analyzed areas26 and the limitations of activation mapping including difficulties in defining local activation in AF,9 small electrode grids that may miss precessing (limited migration of) rotational activity (“wobbles”),28,29 and disorganization of spiral arms emanating from a rotor via “fibrillatory conduction”.18 Focal impulse and rotor modulation (FIRM) uses phase algorithms to track human AF rotors precessing in 2–3 cm2 areas30 whose ablation has been shown by many groups to produce higher long-term freedom from AF than conventional ablation.13,14 It is unclear whether recent reports of rotor instability by other methods15,31 are limited by these factors, or whether recording AF for short periods of seconds may miss stability evident over minutes or longer. We set out to quantify the stability of rotor and focal sources for human AF over prolonged periods to time and
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TABLE 1 Clinical Characteristics of Patients Paroxysmal Persistent AF
Characteristic All patients Age in years, mean (SD) Gender (male/female) Left atrial diameter (mm), mean (SD) LVEF (%), mean (SD) Prior unsuccessful AF ablation Previously failed amiodarone
91 60.5 (11) 74/17 46.7 (9) 59(12) 24.0% (22/91) 16.7% (16/91)
169 62 (11) 147/22 52 (10) 52 (13) 41.2% (72/169) 32.8% (55/169)
P
0.313 0.223 60 days after discontinuing amiodarone (Table 1). Via femoral venous access, a multipolar catheter was placed in the coronary sinus
Figure 1. Panoramic contact mapping of right and left atria for FIRM-guided mapping of AF sources. A: Good right atrial coverage, with conformation of splines to the atrial contour indicating good contact, with one spline near the tricuspid annulus. B: Good left atrial coverage, except for the septum and dilated right pulmonary vein antra in this case (indicated by contour of ablation catheter). Areas of poor electrode contact are represented as continuously black regions on FIRM maps. 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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and a 64 pole basket catheter (Constellation, Boston Scientific Corp., Natick, MA, USA) was advanced sequentially to right then left atria via 8.5F sheaths (Fig. 1) to optimize atrial contact using fluoroscopy, electrography, and/or intracardiac echocardiography. Care was taken to position the right atrial basket in patients with right atrial permanent pacemaker leads.13 Patients presenting in sinus rhythm were paced into AF as described,32 adding isoproterenol if required to induce sustained AF, in which case it was maintained throughout the case. Unipolar signals from the multipolar catheter were filtered at 0.05–500 Hz for digital export from electrophysiological recorders at each site (Bard Pro, Billerica, MA, USA; Cardiolab, GE Medical, Milwaukee, WI, USA). AF Mapping Three-dimensional activation information from the basket (Supplemental figure shows coverage of the vast majority of the atria) was analyzed using a FDA-approved system (RhythmViewTM , Topera Inc., Menlo Park, CA, USA) that uses described algorithms32,33 to map an activation trail of propagation in AF using the rate-response of repolarization,6-10 conduction,4,7 cycle length,9,34 and phase analysis to filter physiological signal from noise. AF was analyzed in multiple 1-minute “epochs” to produce videos (FIRM maps) that were projected onto a grid. We assessed the stability of rotors/sources in multiple recordings over several minutes prior to FIRM-guided ablation.
FIRM-guided or conventional ablation. In FIRM-guided patients, radiofrequency energy was delivered to the region of rotation or focal origin, for ࣈ5–10 minutes per source repeated for all sources, followed by conventional ablation. Conventional ablation1 comprised PV isolation verified using a circular catheter (LassoTM , Biosense Webster, Diamond Bar, CA, USA or Optima, St. Jude Medical, Minnetonka, MN, USA) and linear lesions at the left atrial roof in patients with persistent AF. Other clinically indicated ablation, e.g., of atrial flutter, was performed at the discretion of the operator at each site. Statistical Analysis Continuous data are represented as mean ± standard deviation. The Student’s t-test was used to compare continuous variables between 2 groups, such as the number of rotor cycles. Paired continuous variables were compared using linear regression and the paired t-test. The chi-square test was applied to contingency tables for categorical variables. A P value of 28,421 cycles (=90 × 60,000/190) during mapping. Figure 3 presents a stable left atrial AF rotor with fibrillatory interference of its spiral arms, in a 58-year-old man with paroxysmal AF and no prior ablation. The rotor precessed in a stable region of the mid-posterior left atrium for
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Figure 2. Stable AF rotor with consistent spiral arms. This AF was in a 47-year-old gentleman with persistent AF despite extensive left atrial ablation. A dominant rotor was found in the right atrium (shown) that produced a clockwise emanating spiral wave for over 90 minutes of mapping (>28,421 cycles). Fibrillatory breakdown from the rotor affected only the periphery of the spiral arms (panel A). This rotor was temporospatially stable until eliminated by FIRM-guided ablation. TABLE 2 AF Source Dynamics Characteristics
Paroxysmal
Persistent AF
P
Number of patients FIRM-mapped AF cycle length (coronary sinus), milliseconds
91 194 ± 29 All patients 100% (91/91) 2.7 ± 1.4 1.8 ± 1.1 1.0 ± 0.8
169 183 ± 29
0.005
98.8% (167/169) 2.9 ± 1.4 1.8 ± 1.1 1.2 ± 0.9
4,290 ± 5,847
4,150 ± 6,604
0.543 0.283 0.930 0.083 0.781
4,114 ± 5,836
3,940 ± 7,458
4,681 ± 5,890 Patients with no prior ablation 100% (69/69) 2.7 ± 1.4 1.8 ± 1.1 1.0 ± 0.8
4,509 ± 4,803
4,538 ± 6,372
3,631 ± 5,230
4,304 ± 6,353
3,338 ± 5,499
5,100 ± 6,444
4,162 ± 4,681
No. of patients with detected sources No. of concurrent AF sources No. of LA sources No. of RA sources All sources: no. of cycles mapped Mean ± SD Left atrial sources, no. of cycles mapped Mean ± SD Right atrial sources, no. of cycles mapped Mean ± SD No. of patients with detected sources No. of concurrent AF sources No of LA sources No of RA sources All cycles, no. of cycles mapped Mean ± SD Left atrial sources, no. of cycles mapped Mean ± SD Right atrial sources, no. of cycles mapped Mean ± SD
Percentages are for each population (column-wise). All patients had biatrial mapping.
99% (96/97) 2.9 ± 1.4 1.8 ± 1.1 1.2 ± 0.9
0.795 0.808
1.000 0.283 0.823 0.08 0.094 0.152 0.300
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Figure 3. Stable, spatially precessing rotor (counterclockwise) with varying spiral waves from interaction with fibrillatory activity in a 58-year-old gentleman with paroxysmal AF, left atrial diameter of 60 mm, LVEF 60% and no prior ablation. FIRM mapping revealed a rotor core in the mid-posterior left atrium for > 30 minutes (10,227 cycles). Despite stability of the rotor, the emanating counterclockwise spiral wave (arrows) in both panels showed variable organization due to dynamic cycle-to-cycle interaction with fibrillatory wavelets (lines with block). This rotor was temporospatially stable until eliminated by FIRM-guided ablation. TABLE 3 Regional Distribution of FIRM-Mapped AF Sources Location Left atrium Left atrial roof Anterior left atrium Posterior/inferior left atrium Near left pulmonary veins Near right pulmonary veins Right atrium Lateral Posterior Septal
Paroxysmal (n = 240)
Persistent AF (n = 482)
P
167 (70%) 38 (16%) 32 (13%) 46 (19%) 35 (15%) 16 (7%) 73 (30%) 32 (13%) 27 (11%) 14 (6%)
305 (63%) 72 (15%) 47 (10%) 87 (18%) 61 (13%) 38 (8%) 177 (37%) 87 (18%) 37 (8%) 53 (11%)
0.093 0.778 0.155 0.744 0.492 0.544 0.093 0.100 0.118 0.023
>30 minutes (=30 × 60,000/176 = 10,227 cycles), with spiral arms that disorganized (arrows) via collision from a (separately identified) right atrial rotor and transient rotational spins (“fibrillatory conduction”). Figure 4 presents a rotor in AF induced by pacing; after >45 minutes the AF self-terminated then spontaneously reinitiated in a stable location as indicated.
Source Stability and Regionality AF sources precessed within spatially reproducible regions for all patients during mapping for 4,196 ± 6,360 cycles (Table 2; Figs. 2-5) over tens of minutes. There were no differences in source stability between paroxysmal and persistent AF.
Swarup et al.
Stable Human AF Rotors
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Figure 4. Stability of left atrial rotor in spontaneous versus induced AF. A: FIRM maps of both atria show a left atrial rotor in pacing-induced AF, producing counterclockwise spiral waves (white arrow) in AF. AF terminated and spontaneously reinitiated. Forty-five minutes later, B: FIRM maps show this left atrial rotor in the same region producing a counterclockwise spiral wave. This FIRM map also illustrates transient circular activity in the right atrium (dashed arrow) that was not consistent over time and not diagnosed as a rotor on FIRM mapping. The left atrial rotor was spatiotemporally stable for > 45 minutes (>14,210 cycles) until eliminated by FIRM-guided ablation.
The Supplemental online movie shows a left atrial AF rotor in a 59-year-old man with persistent AF, showing spatial stability for >200 cycles with varying peripheral breakdown. The actual rotor core precesses within the area indicated by the arrows in the mid-posterior left atrial wall, causing slight variations in the rotational path but substantial variation in the peripheral transient rotational spins. This rotor was actually stable for tens of minutes (>3,000 cycles) until ablated in this location outside a typical wide-area PVI lesion set. As shown in Table 3, stable sources lay in multiple biatrial locations near and remote from the PV in patients with paroxysmal as well as persistent AF. Discussion This is the first study to quantify the spatiotemporal dynamics of human AF over prolonged periods of time in terms of rotors, focal sources, and fibrillatory conduction. In this prospective multicenter registry of FIRM, the largest series to date, AF rotors and focal sources were not as “fixed” as atrial tachycardias but precessed for tens of minutes in spatially reproducible areas, i.e., were temporospatially stable. Conversely, emanating activity was variable and fused with fibrillatory conduction. On phase analysis, AF source stability was similar for left versus right atria, for paroxysmal versus persistent AF, and for patients with no prior ablation versus AF despite prior ablation. Rotor stability explains the effectiveness of localized targeted ablation now shown by several groups, while precession and the complex dynamics of fibrillatory conduction may explain differences in the detection or stability of rotors using different techniques. Stable Sources and Fibrillatory Conduction in Human AF This prospective multicenter study further supports localized sources as primary maintaining mechanisms for human AF, as proposed by Mines et al. and Sir Thomas Lewis, then shown in animal models showing spiral waves (rotors).18 There are now several reports on the FIRM of rotors and fo-
cal sources,14,17,35,37 and other groups have shown evidence for human AF rotors using other techniques.15,16,31 Mechanistically, these results demonstrate in a large population that human AF is characterized by organized rotors whose spiral arms disorganize into fibrillatory conduction.18 Therefore, unlike macroreentry around an obstacle, spiral arms are less suitable targets for bisecting linear lesions, although such lesions may still be effective if they are close enough to the rotor core to reduce the elbow room for rotation around the core.38 Studies are needed to define if AF rotor precession is constrained by electrical,27 neural,39 or structural11,12 remodeling, and to define the mechanisms causing fibrillatory conduction. Conversely, in the multiwavelet hypothesis, disorganized waves generate AF without preferred regions or AF driving sources. However, that hypothesis cannot readily explain results from localized, limited ablation. Notably, epicardial mapping showing disorganized activity without sources26 has not mapped wide atrial areas simultaneously, necessary to identify precessing AF sources without the ability to “register” maps from different regions mapped at different time points, but examined areas (60/64 displayed channels. (Bard Pro, Natick, MA); (B) 55/56 displayed channels out of 64 recorded (on Carto, Biosense-Webster, Diamond Bar, CA). Video S2.
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