Focal Impulse and Rotor Modulation (FIRM) for Paroxysmal and Persistent Atrial Fibrillation

ABSTRACT: One reason that ablation for atrial fibrillation (AF) remains suboptimal is that mechanistic targets for energy delivery are imprecise. Despite the ‘triggers’ versus ‘substrate’ debate for AF, ‘triggers’ initiate all arrhythmias and ablation is most successful when it abolishes sustaining mechanisms. Since paroxysmal AF often sustains for hours or even days, longer than most supraventricular tachycardias, its sustaining mechanisms are clearly important. Refocusing ablation on AF-sustaining mechanisms may also circumvent current difficulties in achieving durable isolation of all potential pulmonary vein (PV) and non-PV triggers.Several groups now confirm that paroxysmal and persistent AF are maintained by a relatively small number of stable rotors or focal sources (average 2) that lie in both atria often away from pulmonary veins. Focal Impulse and Rotor Mapping/Modulation (FIRM) has proven able to acutely terminate AF and render it non-inducible, often with very brief energy delivery (<5–10 minutes). Notably, stable sources are different from complex fractionated atrial electrograms (CFAE).

This review focuses on the evidence that stable rotors and focal sources drive paroxysmal AF, as well as persistent AF, where FIRM can substantially reduce the extent of atrial ablation and increase success rates. Local stable sources are not indicated by specific electrogram characteristics.

Key words: atrial fibrillation, paroxysmal, human, ablation, therapy, rotor, focal source, spiral wave 

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Introduction 

As atrial fibrillation (AF) increases in incidence,¹ ablation is increasingly recommended for patients who remain symptomatic despite optimal management.² However, with increasing rigor of post-ablation follow-up, the success rate of a single ablation procedure is setting at 50–60%,³ with many patients requiring several procedures each of which potentially target additional and more extensive atrial regions. One ideal goal would be to mechanistically define AF ablation targets, then achieve the 80–90% success rate obtained routinely for other supraventricular arrhythmias after one procedure.^4-7

After the seminal findings of Haïssaguerre⁸ that ectopic beats from pulmonary veins (PVs) can trigger paroxysmal AF (PAF),² PV isolation is widely used to reduce symptomatic PAF,^2,9-11 although its efficacy with contemporary monitoring is 50–60% after one^9,12,13 and ≈70% after several^2,9,13 procedures. Several factors limit PV isolation, including difficulties in achieving durable isolation,^2,14 frequent triggers outside the PVs,^2,9-11 and the fact that AF-sustaining mechanisms are not defined.^15,16

Recent studies from ourselves²⁰ and independent²¹ laboratories show that paroxysmal AF (and persistent AF) are sustained by a small number of previously unidentified rotors or focal sources. Using Focal Impulse and Rotor Mapping and Modulation (FIRM) of contact electrograms, but not virtual electrograms,^22,23 sources are stable for any one patient for hours, days, and even months. This enabled direct source ablation (FIRM) to rapidly terminate and render AF non-inducible prior to any PV ablation, and to greatly improve AF elimination on long-term follow-up²⁰ in the CONFIRM (Conventional Ablation with or without FIRM) trial. Stable human AF rotors²⁰ have also been reported by others.^21,24-26 Although some centers ablate complex fractionated atrial electrogram (CFAE) during AF,¹⁷ that approach often involves considerable ablation and yields mixed results.^18,19 Notably, we recently found that rotors and focal sources are poorly related to sites of CFAE.

This review summarizes the evidence for stable electrical rotors and focal sources, but not CFAE sites, as sources of paroxysmal AF (and persistent AF), and their role as targets for ablation to achieve long-term maintenance of sinus rhythm.²⁰

Focal Impulse and Rotor Mapping: Approach

Figure 1 shows a photo of the FIRM mapping team in San Diego. We routinely map patient-specific AF sources at electrophysiology study using 64-electrode commercially available basket catheters (Constellation, Boston Scientific) placed into the right then left atrium (Figure 2A) that typically achieve excellent contact (Figure 2B).²⁷ Data are exported for analysis to a computational system (RhythmView^™, Topera Medical). Electrograms from nearly all electrodes are typically useable unless the basket lies within a very large atrium (larger than the 55–60 mm basket).²¹ Analyses use physiologically-adaptive algorithms to analyze AF in terms of bi-atrial action potential duration restitution, oscillations^28-31 and conduction velocity restitution,^30,32 that are particularly relevant since even lone AF patients exhibit conduction slowing,^32,33 repolarization abnormalities,^30,31 and scar³⁴ ‘substrates.’

Diagnostic activation movies are created²⁷ to identify patient-specific AF mechanisms. FIRM ablation then targets sources in the right and left atrium (in either order). Anticoagulation is maintained with heparin to achieve routine ACT targets, and in >200 cases to date, there have been no complications from FIRM.^20,21 FIRM mapping and ablation takes ≈1 hour after IV and left atrial access (Figure 3 shows work flow). In published studies,^16,17 PV isolation was then performed. However, in the authors’ current San Diego protocol, we no longer routinely perform PV isolation after FIRM to eliminate patient-specific, AF-sustaining mechanisms.

Focal Impulse and Rotor Mapping: Results

The three-dimensional atria are projected onto grids (Figure 4), with the right atrium opened vertically through the tricuspid valve and the left atrium opened horizontally through the mitral valve. In the FIRM map (Figure 4A), AF rotors have consistent rotational activity around a center. Focal impulses are identified as centrifugal activation from a point of origin. In Figure 4A, the left atrial AF rotor shows rotation (red-to-blue) around a “core” with distal fibrillatory conduction causing disorganization and/or collision. The axis of the rotor also exhibits “wobble” (Figure 4B), as seen in many dynamical rotational systems, and akin to a spinning top or the earth rotating on its axis. The rotor thus moves rapidly between adjacent anatomic sites (i.e., electrodes) within and between cycles,³⁶ detected via time-of-flight analyses, within ≈1-2 cm² for thousands of cycles (multiple epochs >10–20 minutes). In a subset of subjects who failed conventional ablation and then were re-mapped later for FIRM, AF rotors were stable for months.³⁷ Thus, this stability criterion is critical to exclude transient or unstable activation^23,35 that may represent bystander ‘fibrillatory conduction.’ 

Stable sources were seen in all paroxysmal AF and most persistent AF patients (98% in CONFIRM,²⁰ 100% in recent external validation²¹). Fewer sources are seen in paroxysmal than persistent AF (1.7 ± 0.9 vs. 2.2 ± 1.0; p = 0.03). Sources lie in both atria, with 24% in the right atrium, with a ratio of rotors to focal sources of ≈4:1.^20,21

Focal Impulse and Rotor Modulation (FIRM Ablation): Approach

Since rotors or focal sources are stable, they can be targeted directly for ablation (FIRM) using many energy sources. CONFIRM²⁰ and external studies²¹ used irrigated and non-irrigated radiofrequency and cryoablation energy over the electrodes subtending each source guided by fluoroscopy; if electroanatomic mapping is used, we use fluoroscopy to verify real-time registration accuracy. The acute endpoint of ablation is AF termination or 5–10 minutes of radiofrequency energy application, whichever comes first. In Figure 4B, FIRM alone terminates AF to sinus rhythm in <1 minute. Figure 4D shows a common finding of large areas of CFAE that were unrelated to AF-sustaining sites. In such cases, CFAE-targeted ablation would entail ablating a significant fraction of the atrial endocardium remote from the rotor.

When FIRM terminates AF, vigorous attempts are made to reinduce AF using burst pacing. If AF is non-inducible, then the event is classified as “AF termination/non-inducible” (Figure 5). The composite acute endpoint of all FIRM clinical studies is AF termination/non-inducibility, or AF cycle length prolongation by >10% (indicating elimination of a secondary AF source).^38,39 If AF terminates by FIRM but is then re-inducible, the event is classified as ‘slowing.’ Since 2.1 ± 1.0 sources were observed per patient in the CONFIRM trial, typical total FIRM ablation time is 15–20 minutes. In CONFIRM, FIRM-guided patients then went on to conventional ablation (often in sinus rhythm after AF had been rendered non-inducible) while FIRM-blinded patients received only conventional ablation.

FIRM-Only Ablation: Acutely Terminates and Renders AF Noninducible

Figure 5 shows AF termination by FIRM prior to any other ablation. Vigorous burst pacing was then able to trigger AF, but the atria were no longer capable of sustaining AF when pacing stopped (<2.9 seconds in Figure 5C). The endpoint of termination/non-inducibility, while strict, has been shown to predict very high freedom from AF after conventional⁴⁰ and FIRM²⁰ ablation.

FIRM ablation appears to take less time to achieve AF termination/non-inducibility than other approaches. In a recently presented multicenter FIRM experience⁴¹ (n = 201 patients with FIRM mapping, n = 136 with FIRM-guided ablation), termination/non-inducibility was achieved in 92% of n = 38 paroxysmal AF patients after 6 minutes (median, IQR 2–10 minutes) of FIRM at the primary source, or 11 minutes (IQR 8-22 minutes) of total FIRM. By comparison, in prior paroxysmal AF studies, Jais et al⁴⁰ reported that PV isolation terminated and rendered AF non-inducible in 57% of patients using 36 ± 13 minutes of ablation, and Oral et al reported that PV isolation and left atrial linear lesions terminated and rendered AF non-inducible in 40% of patients after 43 ± 10 minutes of ablation.⁴²

In paroxysmal and persistent AF patients, FIRM ablation alone terminates AF and renders it non-reinducible in 56%²⁰ and 67%²¹ of patients before PV isolation. The composite acute endpoint (termination/non-inducibility and slowing) was achieved by FIRM alone in 86% (31/36) of patients in the FIRM-guided limb of the CONFIRM trial²⁰ and 100% (12/12) of mapped patients in an external series.²¹ Notably, FIRM terminates AF predominantly to sinus rhythm (23/28 terminations in both pooled studies, 82%^20,21), unlike conventional ablation, which terminates nonparoxysmal AF typically to atrial tachycardia.³⁹

A videotaped case of FIRM-guided ablation demonstrating acute AF termination to sinus rhythm with non-inducibility is available as an online video report.⁴³

Long-Term Outcome After FIRM-Guided Ablation at AF Sources: The CONFIRM Trial

The CONFIRM trial (CONventional ablation with or without Focal Impulse and Rotor Modulation) was a prospective case cohort study²⁰ enrolling 92 patients at 107 consecutive AF ablation procedures, the majority (n = 61) of whom had nonparoxysmal AF.

For all patients, single-procedure AF elimination in CONFIRM was higher for FIRM-guided than conventional FIRM-blinded cases (82.4% versus 44.9%; p < 0.001) after 273 days (median; IQR 132–681). Figure 6 illustrates a Kaplan-Meier curve showing benefit for FIRM-guided versus FIRM-blinded cases for patients off anti-arrhythmic medications (p < 0.001). CONFIRM is among the largest AF trials to compare a novel ablation strategy to state-of-the-art conventional ablation^44,45 rather than to failed anti-arrhythmic medications.^9,46,47

The main clinical limitation of CONFIRM is that it was non-randomized, although subjects were enrolled consecutively and treated prospectively for pre-specified endpoints, and FIRM-guided subjects had more comorbidities and more rigorous follow-up (implanted ECG monitors in 88.2% versus 26.1%; p < 0.001) than FIRM-blinded patients. However, these differences should bias against the FIRM-guided limb. By design, CONFIRM included a wide range of patients, including those with prior ablation, and FIRM-guided ablation maintained its benefit over FIRM-blinded therapy in patients at first ablation and all prespecified subgroups. The main mechanistic limitation pointed out in the CONFIRM trial was that PV isolation was also performed in the active (FIRM) limb. Ongoing studies are therefore examining the benefits of FIRM ablation alone.

Conclusions

Atrial fibrillation, like other supraventricular tachycardias, is triggered then sustained by patient-specific mechanisms. Independent laboratories now show that stable rotors and focal sources sustain paroxysmal as well as persistent AF. Elimination of all patient-specific sources by FIRM can terminate AF and render it non-inducible prior to any other ablation, and substantially increase single-procedure freedom over conventional ablation in patients with paroxysmal AF and persistent AF. Notably, rotors and focal sources do not show an electrogram ‘fingerprint,’ but are detectable only by wide-area contact mapping. Ongoing studies are examining the efficacy of FIRM alone to provide high clinical efficacy while minimizing atrial ablation in patients with paroxysmal AF.  

Disclosures: Dr. Krummen and Dr. Narayan report fellowship support from Boston Scientific, Medtronic, St. Jude Medical, BIOTRONIK, and Biosense Webster. Dr. Narayan reports being co-inventor on intellectual property owned by the University of California and licensed to Topera Medical, Inc. Dr. Narayan holds equity in Topera. Topera has not sponsored any research, including that presented here. Dr. Narayan also reports having received honoraria from Medtronic, St. Jude Medical, and BIOTRONIK corporations.

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