J Interv Card Electrophysiol DOI 10.1007/s10840-014-9889-8
Mapping and ablating stable sources for atrial fibrillation: summary of the literature on Focal Impulse and Rotor Modulation (FIRM) Tina Baykaner & Gautam G. Lalani & Amir Schricker & David E. Krummen & Sanjiv M. Narayan
Received: 20 November 2013 / Accepted: 14 February 2014 # Springer Science+Business Media New York 2014
Abstract Atrial fibrillation (AF) is the most common sustained arrhythmia and the most common indication for catheter ablation. However, despite substantial technical advances in mapping and energy delivery, ablation outcomes remain suboptimal. A major limitation to AF ablation is that the areas targeted for ablation are rarely of proven mechanistic importance, in sharp contrast to other arrhythmias in which ablation targets demonstrated mechanisms in each patient. Focal impulse and rotor modulation (FIRM) is a new approach to demonstrate the mechanisms that sustain AF (“substrates”) in each patient that can be used to guide ablation then confirm elimination of each mechanism. FIRM mapping reveals that AF is sustained by 2–3 rotors and focal sources, with a greater number in patients with persistent than paroxysmal AF, lying within spatially reproducible 2.2±1.4-cm2 areas in diverse locations. This temporospatial reproducibility, now confirmed by several groups using various methods, changes the concepts regarding AF-sustaining mechanisms, enabling localized rather than widespread ablation. Mechanistically, the role of rotors and focal sources in sustaining AF has been demonstrated by the acute and chronic success of source (FIRM) ablation alone. Clinically, adding FIRM to conventional ablation substantially improves arrhythmia freedom compared with conventional ablation alone, and ongoing randomized trials are comparing FIRM—ablation with and without conventional ablation to conventional ablation alone. In conclusion, ablation of patient-specific AF-sustaining mechanisms (substrates), as exemplified by FIRM, may be central to substantially improving AF ablation outcomes. T. Baykaner : G. G. Lalani : A. Schricker : D. E. Krummen : S. M. Narayan (*) Department of Medicine, University of California, San Diego, CA 92161, USA e-mail: [email protected]
Keywords Atrial fibrillation . Rotors . Ablation . Focal sources . Substrates . Phase mapping
1 Introduction Despite great technological advances, the treatment of atrial fibrillation (AF) with drug therapy, transvascular, or surgical ablation remains suboptimal [1]. A major challenge in improving outcomes is that our mechanistic understanding of AF is unclear [1]. From the perspective of an interventional cardiac electrophysiologist, eliminating all triggers should eliminate AF, yet in practice, durable pulmonary vein (PV) isolation remains elusive [1], and triggers that arise outside PVs are difficult to rigorously map and ablate [2]. Accordingly, multicenter ablation trials report success of ≈50 % (single procedure) to ≳70 % (multiple procedures) for paroxysmal AF [1], with lower results in persistent AF. A complementary approach is to ablate AF-sustaining mechanisms (substrates) that should in theory render reconnected PVs or other triggers incapable of sustaining AF in each patient. Several modalities now demonstrate atrial fibrosis, low voltage, and other structural substrates in patients with paroxysmal as well as persistent AF. Moreover, several laboratories have recently shown that paroxysmal as well as persistent AF in many patients is sustained by electrical rotors and focal sources in diverse locations in right and left atrium, where localized ablation (focal impulse and rotor modulation (FIRM)) performed alone or with PV isolation can greatly improve long-term arrhythmia freedom. From both a conceptual and practical point of view, FIRM provides an opportunity for defined AF substrate ablation using the wellestablished paradigm of mapping patient-specific mechanisms, targeting them for ablation, then remapping to ensure
J Interv Card Electrophysiol Table 1 Key findings on Focal Impulse and Rotor Modulation (FIRM) 2011–2013 Reference Findings [18, 28]
[27] [17] [10, 32] [25, 33] [34] [17]
CONventional ablation with or without Focal Impulse and Rotor Modulation (CONFIRM) Trial. Clinical trial showing superior efficacy of FIRM+conventional ablation compared with conventional ablation alone Very long-term efficacy. Superior efficacy of FIRM-guided ablation in the CONFIRM trial are maintained at 3 years Multicenter Long-Term Validation of FIRM-guided ablation. Multicenter registry showing that FIRM-guided ablation has a rapid learning curve with similar outcomes to the CONFIRM trial FIRM-guided ablation is effective in patients with traditionally poor outcomes from conventional ablation Success of various strategies for AF ablation can be explained by coincidental or direct elimination of AF rotors and focal sources First multicenter case series of FIRM mapping and ablation; independent case reports of FIRM mapping of atrial tachycardia and AF Spatial stability of rotors identified by FIRM-mapping during prolonged mapping and at successive electrophysiological studies Rotors and focal sources on FIRM-mapping are unrelated to complex fractionated electrograms or sites of low voltage Locations. AF rotors and focal sources lie diversely in left atrium, and one third lie in the right atrium
[23] [23] [35] [36]
Physiological basis for FIRM Mapping and use for mapping AF and atrial tachycardias Practical approach to FIRM-mapping, including basket positioning pearls and pitfalls Biophysical analyses of the resolution required to map human AF rotors Videotaped FIRM-guided case report, with full online case presentation
[29] [30, 31]
their elimination and optimize outcome. This review summarizes and synthesizes the published literature on FIRM mapping and ablation.
2 Historical evidence for discrete AF mechanisms that can be treated Prior mapping of human AF has been detailed yet constrained by limited intraoperative cardiac exposure, undefined tissue dynamics in the human atria, and empirical approaches to eliminate spurious signals (noise reduction), without targeted interventions (such as ablation) that are essential to define AF mechanisms from bystanders. Two major mechanistic concepts are proposed for AF. The disorganization hypothesis postulates that multiple meandering wavelets, numerous intramural waves, or other spatially distributed mechanisms per se sustain AF without underlying drivers. First suggested in computer models by Moe et al., Allessie et al. have since mapped n=49 patients to confirm disorganization in AF, with localized reentry in some patients [3]. However, interventions were not used to perturb AF, and so it remains unclear if disorganization causes AF or results from another mechanism. The maze procedure, often cited to support the disorganization hypothesis, was actually conceived by Schuessler, Cox, Boineau, and collaborators at Washington University to interrupt stable reentrant circuits in diverse locations [4, 5]. Studies supporting the disorganization hypothesis are also limited by studying small samples (100-cm2 left atrial areas in persistent AF by MR imaging [6]), that could not exclude drivers outside the
mapped samples, in patients at surgical valve repair [7] or without clinical AF [3]. Thus, while these studies nicely quantify disorganization in AF, they do not prove that this “drives” AF. The alternative hypothesis of localized sources for AF was shown by Mines and Lewis in the early 1900s, by Schuessler, Cox, and Boineau [4, 5] in seminal work used to design Maze surgery and by Jalife et al [8] who revealed that electrical spiral waves (rotors) can sustain AF. Localized AF sources explain many remarkable clinical observations. Persistent AF can be terminated by localized ablation, rarely even by a single lesion [9, 10] and by catheter pressure at a specific prescribed location [11]; spatial propagation vectors in AF may be consistent [12], and sites of high
Fig. 1 FIRM mapping and ablation protocol
J Interv Card Electrophysiol
rate or dominant frequency are often stable over time [13]. Insightful early mapping studies reported sporadic spiral waves in human atria using invasive wide-area mapping during AF [14] and on transitions from atrial macroreentry to AF [15]. While these common observations are in fact predicted by the localized source hypothesis, they are extremely difficult to reconcile with the spatial disorganization hypothesis.
FIRM uses computational analyses of wide area recordings of AF in both atria and has revealed stable (spatially reproducible) rotors or focal sources in AF in patients with nonvalvular AF. The central mechanistic role of sources has been shown in the multicenter Precise Rotor Elimination without Concomitant pulmonary vein ISolation for the Elimination (PRECISE) trial, in which FIRM-only ablation eliminated AF acutely and on rigorous long-term follow-up [16]. The published literature on FIRM is summarized in Table 1. AF sources on FIRM mapping are typically concurrent, with 2–3 per patient, each occupying≈2-cm2 areas in right as well as in left atrium [17]. In the conventional ablation with or without FIRM (CONFIRM) trial and other series, FIRM-
guided plus conventional ablation improved AF elimination to 82.4 from 44.9 % for conventional ablation alone using predominantly implantable loop recorders [18, 19]. These results have now been reported in several hundred patients at over a dozen centers [18, 19], while AF rotors have now been revealed by additional investigators using diverse approaches [20–22]. A FIRM procedure involves iteratively mapping and ablating patient-specific AF rotors and focal sources until all sources are eliminated in the right and left atria. Since FIRM mapping is tailored to AF in each patient, one prerequisite is to actually obtain AF. In patients with paroxysmal AF who present sinus rhythm, AF is induced by rapid pacing or isoproterenol [18]. Several recent studies show that AF exhibits spatial and temporal similarities whether induced or spontaneous (akin to many other arrhythmias) [23]. FIRM records AF widely from both atria, since AF is highly spatially nonuniform, using a multipolar contact catheter to best detect low amplitude AF signals. Computational methods are then used to map propagation, using prior studies of human atrial repolarization and conduction dynamics to physiologically separate signal from noise. AF is analyzed in 1-min recordings in multiple epochs spanning 5–10 min. Ablation then targets identified rotors or focal sources until they are eliminated [23]. This is summarized in Fig. 1.
Fig. 2 Spatial reproducibility of AF rotor locations over time within small precession areas. a Left atrial rotor, counterclockwise in the high posterolateral wall. b Using phase mapping, the rotor core precesses in a 3.2-cm2 region over time. c This same rotor was stable at 90 min later, until ablated. d Right atrial rotor, clockwise in the lateral wall. e Rotor core precession in a limited area (3.1 cm2) of that right atrial rotor f was
stable 1 h later, until eliminated by FIRM ablation. Right atrium: top superior vena cava, bottom inferior vena cava, left lateral tricuspid valve, right medial tricuspid valve. Left atrium: top superior mitral annulus, bottom inferior mitral annulus, left septal, right lateral. Dots indicate stylized electrode locations (Modified from Narayan et al. [25], with permission)
3 Identifying AF sources in individual patients: focal impulse and rotor mapping (FIRM)
J Interv Card Electrophysiol
FIRM mapping reveals that paroxysmal and persistent AF are sustained by 2.1±1.1 to 2.3±0.9 concurrent rotor or focal sources in essentially all patients (97 [18] to 100 % [10, 19]), with a higher number of sources in persistent than paroxysmal AF [18]. Rotors and focal sources control activation in their immediate vicinity [17] that disorganizes peripherally (fibrillatory conduction). The AF rotor core is not fixed as in microreentrant atrial tachycardia [24] but precesses [8] to interrupt rotation on simple activation analysis, requiring phase mapping [17, 25] for detection (Fig. 2). It is notable that AF sources lie in right as well as in left atrium. In each chamber, locations are diverse and patientspecific (Fig. 3), with≈40–50 % lying near PVs (22.8 %) and the left atrial roof (16 %), 28 % elsewhere in left atrium and
Fig. 3 Biatrial rotor locations for a paroxysmal and b persistent AF (From Narayan et al. [17], with permission)
33 % in right atrium, with a more widespread distribution in persistent compared with paroxysmal AF. This may explain the greater success of widespread ablation in persistent and longstanding persistent AF patients [17]. Further work is required to determine what structural, anatomical [26], or functional mechanisms cause the formation and potential progression of AF sources in each patient.
4 FIRM-guided ablation Targeted ablation of patient-specific AF rotors is feasible because they are spatially reproducible (i.e., precess in small areas) and temporally reproducible (can be captured in short duration recordings), unlike transient or migratory processes. FIRM-guided ablation targets the region of source precession, each occupying 2.2±1.4 cm2 [17] and requiring≈5 min of ablation time [10, 18, 19]. This is repeated for all sources for an average of 15–20 min of total FIRM ablation time [10, 18, 19]. Figure 4 illustrates a typical FIRM-guided ablation case. FIRM-guided ablation was compared with conventional ablation in the CONFIRM trial that enrolled 92 patients at 107 procedures of whom 72 % had persistent AF. Patients were prospectively treated, in a two-arm 1:2 design, by ablation at sources (FIRM-guided) followed by conventional ablation (n=36) or conventional ablation alone (n=71; FIRMblinded). The total time required for FIRM-guided ablation at all sources was 16.1±9.8 min. On long-term follow-up after a single procedure (median 273 days, IQR 132 to 681 days), FIRM-guided cases had higher freedom from AF (82.4 vs 44.9 %; p10 independent laboratories confirm these results [10, 19], while early studies show that the benefits of FIRMguided over conventional ablation are maintained for over 3 years of follow-up. Finally, as mechanistic proof of the efficacy of substrate ablation even in paroxysmal AF, the multicenter PRECISE trial of AF showed that FIRM-only ablation provided 82.6 % freedom from AF after a single procedure in patients with paroxysmal AF [16]. For further mechanistic validation, this approach is being tested in
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Fig. 4 Successive elimination of AF sources by firm-mapping/ablation/ remapping in a man with persistent AF, a right atrial contact basket mapping revealed b a rotor with electrograms shown in c that was successfully ablated. d Subsequent FIRM maps showed elimination of
all sources in the right atrium. e Left atrial contact basket mapping revealed f a high posterior wall rotor (electrograms (g)) that was also successfully ablated. The patient is AF-free on rigorous monitoring over 18 months (From Narayan et al. [36], with permission)
ongoing randomized multicenter clinical trials against conventional ablation.
shows a case in which two left atrial rotors were ablated by FIRM. Conventional wide-area circumferential ablation would have naturally passed through the superior but, without the benefit of FIRM mapping, not the inferior rotor. In a preplanned on-treatment analysis, we investigated whether such coincidental rotor ablation influenced outcome, by comparing source locations to ablation lesion positions blinded to outcome. When ablation passed through AF sources (directly by FIRM or coincidentally by anatomical ablation), freedom from AF was 80.3 %, while when ablation missed all sources, the success was 18.8 %. Freedom from AF was highest when all sources were eliminated, intermediate when some were eliminated, and lowest when all were missed. Sites of localized sources did not show a specific electrogram fingerprint [17]. Even in cases where rotors overlay complex fractionated atrial electrogram (CFAE) sites, additional sites of CFAE were frequently noted at distant locations. This corresponds with clinical experience in which ablation of CFAE is sometimes dramatically effective and in other times does not appear to have impact.
5 Relationship of AF rotors and focal sources to traditional ablation sites and complex fractionated atrial electrograms Since rotors are present in diverse locations a priori, we hypothesized that rotor ablation may explain the success of conventional as well as FIRM-guided ablation [17]. Figure 6
6 Future studies Fig. 5 Freedom from AF after a single FIRM+conventional ablation procedure (blue) compared with a single conventional ablation procedure (red). First ablation cases are shown in dashed lines. Implanted loop recorders were implanted in 88.2 % of FIRM-guided cases (From Narayan et al. [18], with permission)
While current multicenter studies show improved efficacy from FIRM-guided compared with conventional ablation, various FIRM-guided ablation strategies should be tested against conventional ablation in randomized multicenter trials
J Interv Card Electrophysiol Fig. 6 Conventional ablation (wide area circumferential ablation, WACA) can pass through or miss AF rotor sites (Modified from Narayanet al. [17], with permission)
in different populations. Similarly, studies of FIRM-guided ablation have thus far shown no disturbing safety issues, with no reported perforations, thromboemboli, nor other complications resulting from basket recordings or FIRM-guided ablation. Indeed, since rotors in many patients actually lie away from the posterior left atrium or phrenic nerves, FIRM-guided ablation may actually reduce the risk of damage to these structures compared with ablation that consistently targets these regions. Clearly, this safety profile must be confirmed in randomized trials. When rotor and focal sources do lie near these sensitive structures, the same precautions used for PV isolation or empiric linear lesions should be taken (in the CONFIRM trial, for instance, a minority of rotor sites were accordingly left unablated [18, 19]). Equally importantly, mechanistic studies are needed to determine what structural, anatomical [26], or functional mechanisms cause the formation and potential progression of AF sources in each patient. Together, these studies will further strengthen the mechanistic underpinnings and optimal clinical utility of FIRM-guided ablation at rotors and focal sources.
7 Conclusions A rapidly growing body of literature shows that nonvalvular paroxysmal and persistent AF are sustained by stable rotors and focal sources on FIRM mapping. The mechanistic role of these sources is demonstrated by the long-term elimination of AF by their ablation alone. Clinically, FIRM reveals two to three concurrent sources lying in patient-specific stable≈2cm2 areas in right as well as in left atrium. Briefly, targeted ablation at sources has been shown in multicenter studies to greatly improve AF outcomes over conventional ablation
alone. Future studies should explain why rotors form in patient-specific locations and should compare FIRM-only ablation to conventional ablation in randomized clinical trials. Both lines of investigation are ongoing. Acknowledgments This work was supported by grants to S.M. Narayan from the NIH (HL83359 and HL103800). Conflict of interest Dr. Narayan is a 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, and Biotronik. The other authors report no conflicts.
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atrial fibrillation: extended multi-center experience (abstract). in review 20. Ganesan, A. N., Kuklik, P., Lau, D. H., et al. (2013). Bipolar electrogram shannon entropy at sites of rotational activation: implications for ablation of atrial fibrillation. Circulation Arrhythmia and Electrophysiology, 6, 48–57. 21. Haissaguerre, M., Hocini, M., Shah, A. J., et al. (2013). Noninvasive panoramic mapping of human atrial fibrillation mechanisms: a feasibility report. Journal of Cardiovascular Electrophysiology, 24, 711– 717. 22. Lin, Y. J., Lo, M. T., Lin, C., et al. (2013). Prevalence, characteristics, mapping, and catheter ablation of potential rotors in nonparoxysmal atrial fibrillation. Circulation. Arrhythmia and Electrophysiology, 6, 851–858. 23. Narayan, S. M., Krummen, D. E., & Rappel, W.-J. (2012). Clinical mapping approach to identify rotors and focal beats in human atrial fibrillation. J Cardiovascular Electrophysiology, 23, 447–454. 24. Haddad, M.E., Houben, R., Tavernier, R., Duytschaever, M. (2014). A stable reentrant circuit with spiral wave activation driving atrial tachycardia. Heart Rhythm in press. 25. Narayan, S. M., Krummen, D. E., Enyeart, M. W., & Rappel, W. (2012). Computational mapping approach identifies stable and longlived electrical rotors and focal sources in human atrial fibrillation. PLos ONE, 7, e46034. 26. Oakes, R. S., Badger, T. J., Kholmovski, E. G., et al. (2009). Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation, 119, 1758–1767. 27. Baykaner, T., Clopton, P., Schricker, A.A., Lalani, G., Krummen, D.E., Narayan, S.M. (2013). Targeted ablation at stable atrial fibrillation sources improves success over conventional ablation in high risk patients: a substudy of the CONFIRM trial. Canadian J Cardiology, 29(10), 1218–26. 28. Narayan, S.M., Shivkumar, K., Mittal, S., et al. (2011). CONventional ablation for atrial fibrillation with or without Focal Impulse and Rotor Modulation: the CONFIRM trial (Late Breaking Clinical Trial Abstract). Heart Rhythm, 8, LB-04. 29. Narayan, S.M., Baykaner, T., Clopton, P., et al. (2014). Ablation of rotor and focal sources reduces late recurrence of atrial fibrillation compared to trigger ablation alone: extended follow up of the CONFIRM (CONventional ablation with or without Focal Impulse and Rotor Modulation) trial. Journal of the American College of Cardioliology in press. 30. Miller, J.M., Daubert, J., Day, J., et al. (2013). Long-term results of patients receiving Focal Impulse and Rotor Modulation (FIRM) for atrial fibrillation: extended multi-center experience (abstract). Circulation, 128. 31. Kowal, R. C., Daubert, J., Day, J., et al. (2013). Results of Focal Impulse and Rotor Modulation (FIRM) for atrial fibrillation Are equivalent between patients treated in San Diego compared with sites new to FIRM ablation: an extended multi-center experience (abstract). Heart Rhythm, 10, S479. 32. Orlov, M. V., Gorev, M. V., & Griben, A. (2013). Rotors of truly atypical atrial flutters visualized by FIRM mapping and 3D-MRI overlay on live fluoroscopy. Journal of Interventional Cardiac Electrophysiology, 38, 167. 33. Swarup, V., Kowal, R. C., Daubert, J., et al. (2013). Rotors on Focal Impulse and Rotor Mapping are stable over thousands of cycles. Heart Rhythm, 10, S479. 34. Narayan, S. M., Shivkumar, K., Krummen, D. E., Miller, J. M., & Rappel, W.-J. (2013). Panoramic electrophysiological mapping but not individual electrogram morphology identifies sustaining sites for human atrial fibrillation: stable atrial fibrillation rotors and focal sources relate poorly to fractionated electrograms (AF rotors and
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36. Narayan, S. M., Patel, J., Mulpuru, S. K., & Krummen, D. E. (2012). Focal Impulse and Rotor Modulation (FIRM) of Sustaining rotors abruptly terminates persistent atrial fibrillation to sinus rhythm with elimination on follow-up. Heart Rhythm, 9, 1436– 1439.
Mapping and ablating stable sources for atrial fibrillation: summary of the literature on Focal Impulse and Rotor Modulation (FIRM) Tina Baykaner & Gautam G. Lalani & Amir Schricker & David E. Krummen & Sanjiv M. Narayan
Received: 20 November 2013 / Accepted: 14 February 2014 # Springer Science+Business Media New York 2014
Abstract Atrial fibrillation (AF) is the most common sustained arrhythmia and the most common indication for catheter ablation. However, despite substantial technical advances in mapping and energy delivery, ablation outcomes remain suboptimal. A major limitation to AF ablation is that the areas targeted for ablation are rarely of proven mechanistic importance, in sharp contrast to other arrhythmias in which ablation targets demonstrated mechanisms in each patient. Focal impulse and rotor modulation (FIRM) is a new approach to demonstrate the mechanisms that sustain AF (“substrates”) in each patient that can be used to guide ablation then confirm elimination of each mechanism. FIRM mapping reveals that AF is sustained by 2–3 rotors and focal sources, with a greater number in patients with persistent than paroxysmal AF, lying within spatially reproducible 2.2±1.4-cm2 areas in diverse locations. This temporospatial reproducibility, now confirmed by several groups using various methods, changes the concepts regarding AF-sustaining mechanisms, enabling localized rather than widespread ablation. Mechanistically, the role of rotors and focal sources in sustaining AF has been demonstrated by the acute and chronic success of source (FIRM) ablation alone. Clinically, adding FIRM to conventional ablation substantially improves arrhythmia freedom compared with conventional ablation alone, and ongoing randomized trials are comparing FIRM—ablation with and without conventional ablation to conventional ablation alone. In conclusion, ablation of patient-specific AF-sustaining mechanisms (substrates), as exemplified by FIRM, may be central to substantially improving AF ablation outcomes. T. Baykaner : G. G. Lalani : A. Schricker : D. E. Krummen : S. M. Narayan (*) Department of Medicine, University of California, San Diego, CA 92161, USA e-mail: [email protected]
Keywords Atrial fibrillation . Rotors . Ablation . Focal sources . Substrates . Phase mapping
1 Introduction Despite great technological advances, the treatment of atrial fibrillation (AF) with drug therapy, transvascular, or surgical ablation remains suboptimal [1]. A major challenge in improving outcomes is that our mechanistic understanding of AF is unclear [1]. From the perspective of an interventional cardiac electrophysiologist, eliminating all triggers should eliminate AF, yet in practice, durable pulmonary vein (PV) isolation remains elusive [1], and triggers that arise outside PVs are difficult to rigorously map and ablate [2]. Accordingly, multicenter ablation trials report success of ≈50 % (single procedure) to ≳70 % (multiple procedures) for paroxysmal AF [1], with lower results in persistent AF. A complementary approach is to ablate AF-sustaining mechanisms (substrates) that should in theory render reconnected PVs or other triggers incapable of sustaining AF in each patient. Several modalities now demonstrate atrial fibrosis, low voltage, and other structural substrates in patients with paroxysmal as well as persistent AF. Moreover, several laboratories have recently shown that paroxysmal as well as persistent AF in many patients is sustained by electrical rotors and focal sources in diverse locations in right and left atrium, where localized ablation (focal impulse and rotor modulation (FIRM)) performed alone or with PV isolation can greatly improve long-term arrhythmia freedom. From both a conceptual and practical point of view, FIRM provides an opportunity for defined AF substrate ablation using the wellestablished paradigm of mapping patient-specific mechanisms, targeting them for ablation, then remapping to ensure
J Interv Card Electrophysiol Table 1 Key findings on Focal Impulse and Rotor Modulation (FIRM) 2011–2013 Reference Findings [18, 28]
[27] [17] [10, 32] [25, 33] [34] [17]
CONventional ablation with or without Focal Impulse and Rotor Modulation (CONFIRM) Trial. Clinical trial showing superior efficacy of FIRM+conventional ablation compared with conventional ablation alone Very long-term efficacy. Superior efficacy of FIRM-guided ablation in the CONFIRM trial are maintained at 3 years Multicenter Long-Term Validation of FIRM-guided ablation. Multicenter registry showing that FIRM-guided ablation has a rapid learning curve with similar outcomes to the CONFIRM trial FIRM-guided ablation is effective in patients with traditionally poor outcomes from conventional ablation Success of various strategies for AF ablation can be explained by coincidental or direct elimination of AF rotors and focal sources First multicenter case series of FIRM mapping and ablation; independent case reports of FIRM mapping of atrial tachycardia and AF Spatial stability of rotors identified by FIRM-mapping during prolonged mapping and at successive electrophysiological studies Rotors and focal sources on FIRM-mapping are unrelated to complex fractionated electrograms or sites of low voltage Locations. AF rotors and focal sources lie diversely in left atrium, and one third lie in the right atrium
[23] [23] [35] [36]
Physiological basis for FIRM Mapping and use for mapping AF and atrial tachycardias Practical approach to FIRM-mapping, including basket positioning pearls and pitfalls Biophysical analyses of the resolution required to map human AF rotors Videotaped FIRM-guided case report, with full online case presentation
[29] [30, 31]
their elimination and optimize outcome. This review summarizes and synthesizes the published literature on FIRM mapping and ablation.
2 Historical evidence for discrete AF mechanisms that can be treated Prior mapping of human AF has been detailed yet constrained by limited intraoperative cardiac exposure, undefined tissue dynamics in the human atria, and empirical approaches to eliminate spurious signals (noise reduction), without targeted interventions (such as ablation) that are essential to define AF mechanisms from bystanders. Two major mechanistic concepts are proposed for AF. The disorganization hypothesis postulates that multiple meandering wavelets, numerous intramural waves, or other spatially distributed mechanisms per se sustain AF without underlying drivers. First suggested in computer models by Moe et al., Allessie et al. have since mapped n=49 patients to confirm disorganization in AF, with localized reentry in some patients [3]. However, interventions were not used to perturb AF, and so it remains unclear if disorganization causes AF or results from another mechanism. The maze procedure, often cited to support the disorganization hypothesis, was actually conceived by Schuessler, Cox, Boineau, and collaborators at Washington University to interrupt stable reentrant circuits in diverse locations [4, 5]. Studies supporting the disorganization hypothesis are also limited by studying small samples (100-cm2 left atrial areas in persistent AF by MR imaging [6]), that could not exclude drivers outside the
mapped samples, in patients at surgical valve repair [7] or without clinical AF [3]. Thus, while these studies nicely quantify disorganization in AF, they do not prove that this “drives” AF. The alternative hypothesis of localized sources for AF was shown by Mines and Lewis in the early 1900s, by Schuessler, Cox, and Boineau [4, 5] in seminal work used to design Maze surgery and by Jalife et al [8] who revealed that electrical spiral waves (rotors) can sustain AF. Localized AF sources explain many remarkable clinical observations. Persistent AF can be terminated by localized ablation, rarely even by a single lesion [9, 10] and by catheter pressure at a specific prescribed location [11]; spatial propagation vectors in AF may be consistent [12], and sites of high
Fig. 1 FIRM mapping and ablation protocol
J Interv Card Electrophysiol
rate or dominant frequency are often stable over time [13]. Insightful early mapping studies reported sporadic spiral waves in human atria using invasive wide-area mapping during AF [14] and on transitions from atrial macroreentry to AF [15]. While these common observations are in fact predicted by the localized source hypothesis, they are extremely difficult to reconcile with the spatial disorganization hypothesis.
FIRM uses computational analyses of wide area recordings of AF in both atria and has revealed stable (spatially reproducible) rotors or focal sources in AF in patients with nonvalvular AF. The central mechanistic role of sources has been shown in the multicenter Precise Rotor Elimination without Concomitant pulmonary vein ISolation for the Elimination (PRECISE) trial, in which FIRM-only ablation eliminated AF acutely and on rigorous long-term follow-up [16]. The published literature on FIRM is summarized in Table 1. AF sources on FIRM mapping are typically concurrent, with 2–3 per patient, each occupying≈2-cm2 areas in right as well as in left atrium [17]. In the conventional ablation with or without FIRM (CONFIRM) trial and other series, FIRM-
guided plus conventional ablation improved AF elimination to 82.4 from 44.9 % for conventional ablation alone using predominantly implantable loop recorders [18, 19]. These results have now been reported in several hundred patients at over a dozen centers [18, 19], while AF rotors have now been revealed by additional investigators using diverse approaches [20–22]. A FIRM procedure involves iteratively mapping and ablating patient-specific AF rotors and focal sources until all sources are eliminated in the right and left atria. Since FIRM mapping is tailored to AF in each patient, one prerequisite is to actually obtain AF. In patients with paroxysmal AF who present sinus rhythm, AF is induced by rapid pacing or isoproterenol [18]. Several recent studies show that AF exhibits spatial and temporal similarities whether induced or spontaneous (akin to many other arrhythmias) [23]. FIRM records AF widely from both atria, since AF is highly spatially nonuniform, using a multipolar contact catheter to best detect low amplitude AF signals. Computational methods are then used to map propagation, using prior studies of human atrial repolarization and conduction dynamics to physiologically separate signal from noise. AF is analyzed in 1-min recordings in multiple epochs spanning 5–10 min. Ablation then targets identified rotors or focal sources until they are eliminated [23]. This is summarized in Fig. 1.
Fig. 2 Spatial reproducibility of AF rotor locations over time within small precession areas. a Left atrial rotor, counterclockwise in the high posterolateral wall. b Using phase mapping, the rotor core precesses in a 3.2-cm2 region over time. c This same rotor was stable at 90 min later, until ablated. d Right atrial rotor, clockwise in the lateral wall. e Rotor core precession in a limited area (3.1 cm2) of that right atrial rotor f was
stable 1 h later, until eliminated by FIRM ablation. Right atrium: top superior vena cava, bottom inferior vena cava, left lateral tricuspid valve, right medial tricuspid valve. Left atrium: top superior mitral annulus, bottom inferior mitral annulus, left septal, right lateral. Dots indicate stylized electrode locations (Modified from Narayan et al. [25], with permission)
3 Identifying AF sources in individual patients: focal impulse and rotor mapping (FIRM)
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FIRM mapping reveals that paroxysmal and persistent AF are sustained by 2.1±1.1 to 2.3±0.9 concurrent rotor or focal sources in essentially all patients (97 [18] to 100 % [10, 19]), with a higher number of sources in persistent than paroxysmal AF [18]. Rotors and focal sources control activation in their immediate vicinity [17] that disorganizes peripherally (fibrillatory conduction). The AF rotor core is not fixed as in microreentrant atrial tachycardia [24] but precesses [8] to interrupt rotation on simple activation analysis, requiring phase mapping [17, 25] for detection (Fig. 2). It is notable that AF sources lie in right as well as in left atrium. In each chamber, locations are diverse and patientspecific (Fig. 3), with≈40–50 % lying near PVs (22.8 %) and the left atrial roof (16 %), 28 % elsewhere in left atrium and
Fig. 3 Biatrial rotor locations for a paroxysmal and b persistent AF (From Narayan et al. [17], with permission)
33 % in right atrium, with a more widespread distribution in persistent compared with paroxysmal AF. This may explain the greater success of widespread ablation in persistent and longstanding persistent AF patients [17]. Further work is required to determine what structural, anatomical [26], or functional mechanisms cause the formation and potential progression of AF sources in each patient.
4 FIRM-guided ablation Targeted ablation of patient-specific AF rotors is feasible because they are spatially reproducible (i.e., precess in small areas) and temporally reproducible (can be captured in short duration recordings), unlike transient or migratory processes. FIRM-guided ablation targets the region of source precession, each occupying 2.2±1.4 cm2 [17] and requiring≈5 min of ablation time [10, 18, 19]. This is repeated for all sources for an average of 15–20 min of total FIRM ablation time [10, 18, 19]. Figure 4 illustrates a typical FIRM-guided ablation case. FIRM-guided ablation was compared with conventional ablation in the CONFIRM trial that enrolled 92 patients at 107 procedures of whom 72 % had persistent AF. Patients were prospectively treated, in a two-arm 1:2 design, by ablation at sources (FIRM-guided) followed by conventional ablation (n=36) or conventional ablation alone (n=71; FIRMblinded). The total time required for FIRM-guided ablation at all sources was 16.1±9.8 min. On long-term follow-up after a single procedure (median 273 days, IQR 132 to 681 days), FIRM-guided cases had higher freedom from AF (82.4 vs 44.9 %; p10 independent laboratories confirm these results [10, 19], while early studies show that the benefits of FIRMguided over conventional ablation are maintained for over 3 years of follow-up. Finally, as mechanistic proof of the efficacy of substrate ablation even in paroxysmal AF, the multicenter PRECISE trial of AF showed that FIRM-only ablation provided 82.6 % freedom from AF after a single procedure in patients with paroxysmal AF [16]. For further mechanistic validation, this approach is being tested in
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Fig. 4 Successive elimination of AF sources by firm-mapping/ablation/ remapping in a man with persistent AF, a right atrial contact basket mapping revealed b a rotor with electrograms shown in c that was successfully ablated. d Subsequent FIRM maps showed elimination of
all sources in the right atrium. e Left atrial contact basket mapping revealed f a high posterior wall rotor (electrograms (g)) that was also successfully ablated. The patient is AF-free on rigorous monitoring over 18 months (From Narayan et al. [36], with permission)
ongoing randomized multicenter clinical trials against conventional ablation.
shows a case in which two left atrial rotors were ablated by FIRM. Conventional wide-area circumferential ablation would have naturally passed through the superior but, without the benefit of FIRM mapping, not the inferior rotor. In a preplanned on-treatment analysis, we investigated whether such coincidental rotor ablation influenced outcome, by comparing source locations to ablation lesion positions blinded to outcome. When ablation passed through AF sources (directly by FIRM or coincidentally by anatomical ablation), freedom from AF was 80.3 %, while when ablation missed all sources, the success was 18.8 %. Freedom from AF was highest when all sources were eliminated, intermediate when some were eliminated, and lowest when all were missed. Sites of localized sources did not show a specific electrogram fingerprint [17]. Even in cases where rotors overlay complex fractionated atrial electrogram (CFAE) sites, additional sites of CFAE were frequently noted at distant locations. This corresponds with clinical experience in which ablation of CFAE is sometimes dramatically effective and in other times does not appear to have impact.
5 Relationship of AF rotors and focal sources to traditional ablation sites and complex fractionated atrial electrograms Since rotors are present in diverse locations a priori, we hypothesized that rotor ablation may explain the success of conventional as well as FIRM-guided ablation [17]. Figure 6
6 Future studies Fig. 5 Freedom from AF after a single FIRM+conventional ablation procedure (blue) compared with a single conventional ablation procedure (red). First ablation cases are shown in dashed lines. Implanted loop recorders were implanted in 88.2 % of FIRM-guided cases (From Narayan et al. [18], with permission)
While current multicenter studies show improved efficacy from FIRM-guided compared with conventional ablation, various FIRM-guided ablation strategies should be tested against conventional ablation in randomized multicenter trials
J Interv Card Electrophysiol Fig. 6 Conventional ablation (wide area circumferential ablation, WACA) can pass through or miss AF rotor sites (Modified from Narayanet al. [17], with permission)
in different populations. Similarly, studies of FIRM-guided ablation have thus far shown no disturbing safety issues, with no reported perforations, thromboemboli, nor other complications resulting from basket recordings or FIRM-guided ablation. Indeed, since rotors in many patients actually lie away from the posterior left atrium or phrenic nerves, FIRM-guided ablation may actually reduce the risk of damage to these structures compared with ablation that consistently targets these regions. Clearly, this safety profile must be confirmed in randomized trials. When rotor and focal sources do lie near these sensitive structures, the same precautions used for PV isolation or empiric linear lesions should be taken (in the CONFIRM trial, for instance, a minority of rotor sites were accordingly left unablated [18, 19]). Equally importantly, mechanistic studies are needed to determine what structural, anatomical [26], or functional mechanisms cause the formation and potential progression of AF sources in each patient. Together, these studies will further strengthen the mechanistic underpinnings and optimal clinical utility of FIRM-guided ablation at rotors and focal sources.
7 Conclusions A rapidly growing body of literature shows that nonvalvular paroxysmal and persistent AF are sustained by stable rotors and focal sources on FIRM mapping. The mechanistic role of these sources is demonstrated by the long-term elimination of AF by their ablation alone. Clinically, FIRM reveals two to three concurrent sources lying in patient-specific stable≈2cm2 areas in right as well as in left atrium. Briefly, targeted ablation at sources has been shown in multicenter studies to greatly improve AF outcomes over conventional ablation
alone. Future studies should explain why rotors form in patient-specific locations and should compare FIRM-only ablation to conventional ablation in randomized clinical trials. Both lines of investigation are ongoing. Acknowledgments This work was supported by grants to S.M. Narayan from the NIH (HL83359 and HL103800). Conflict of interest Dr. Narayan is a 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, and Biotronik. The other authors report no conflicts.
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