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

David E. Krummen, MD, Thomas McGarry, MD, Marian Holland, MD, and Sanjiv M. Narayan, MD, PhD, MSc University of California and Veterans’ Affairs Healthcare System San Diego, California
David E. Krummen, MD, Thomas McGarry, MD, Marian Holland, MD, and Sanjiv M. Narayan, MD, PhD, MSc University of California and Veterans’ Affairs Healthcare System San Diego, California

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 one9,12,13 and ≈70% after several2,9,13 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, oscillations28-31 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 activation23,35 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 ablation44,45 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.

References

  1. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119-125.
  2. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Heart Rhythm. 2012;9:632-696.
  3. Cosedis Nielsen J, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med. 2012;367:1587-1595.
  4. Feld GK, Fleck RP, Chen PS, et al. Radiofrequency catheter ablation for the treatment of human type 1 atrial flutter: identification of a critical zone in the re-entrant circuit by endocardial mapping techniques. Circulation. 1992;86:1233-1240.
  5. Jackman WM, Wang XZ, Friday KJ, et al. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current. N Engl J Med. 1991;324:1605-1611.
  6. Jackman WM, Beckman KJ, McClelland JH, et al. Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slow-pathway conduction. N Engl J Med. 1992;327:313-318.
  7. Saoudi N, Nair M, Abdelazziz A, et al. Electrocardiographic patterns and results of radiofrequency catheter ablation of clockwise type I atrial flutter. J Cardiovasc Electrophysiol. 1996;7:931-942.
  8. Haïssaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659-666.
  9. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA. 2010;303:333-340.
  10. Oral H, Chugh A, Good E, et al. Randomized comparison of encircling and nonencircling left atrial ablation for chronic atrial fibrillation. Heart Rhythm. 2005;2:1165-1172.
  11. Elayi CS, Di Biase L, Barrett C, et al. Atrial fibrillation termination as a procedural endpoint during ablation in long-standing persistent atrial fibrillation. Heart Rhythm. 2010;7:1216-1223.
  12. Morillo C, Verma A, Natale A. Radiofrequency ablation vs antiarrhythmic drugs as first-line therapy of atrial fibrillation (RAAFT 2) trial (abstract). Heart Rhythm. 2012:Abstract.
  13. Nielsen JC, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med. 2012;367:1587-1595.
  14. Reddy VY, Shah D, Kautzner J, et al. The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study. Heart Rhythm. 2012;9:1789-1795.
  15. Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002;415:219-226.
  16. Vaquero M, Calvo D, Jalife J. Cardiac fibrillation: from ion channels to rotors in the human heart. Heart Rhythm. 2008;5:872-879.
 

  1. Scherr D, Dalal D, Cheema A, et al. Long- and short-term temporal stability of complex fractionated atrial electrograms in human left atrium during atrial fibrillation. J Cardiovasc Electrophysiol. 2009;20:13-21.
  2. Oral H, Chugh A, Yoshida K, et al. A randomized assessment of the incremental role of ablation of complex fractionated atrial electrograms after antral pulmonary vein isolation for long-lasting persistent atrial fibrillation. J Am Coll Cardiol. 2009;53:782-789.
  3. Hayward RM, Upadhyay GA, Mela T, et al. Pulmonary vein isolation with complex fractionated atrial electrogram ablation for paroxysmal and nonparoxysmal atrial fibrillation: a meta-analysis. Heart Rhythm. 2011;8:994-1000.
  4. Narayan SM, Krummen DE, Shivkumar K, et al. Treatment of atrial fibrillation by the ablation of localized sources: the conventional ablation for atrial fibrillation with or without focal impulse and rotor modulation (CONFIRM) trial. J Am Coll Cardiol. 2012;60:628-636.
  5. Shivkumar K, Ellenbogen KA, Hummel JD, et al. Acute termination of human atrial fibrillation by identification and catheter ablation of localized rotors and sources: first multicenter experience of focal impulse and rotor modulation (FIRM) ablation. J Cardiovasc Electrophysiol. 2012 Aug 29.
  6. Schilling RJ, Kadish AH, Peters NS, et al. Endocardial mapping of atrial fibrillation in the human right atrium using a non-contact catheter. Eur Heart J. 2000;21:550-564.
  7. Cuculich PS, Wang Y, Lindsay BD, et al. Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. Circulation. 2010;122:1364-1372.
  8. Ganesan AN, Kuklik P, Lau DH, et al. Bipolar electrogram shannon entropy at sites of rotational activation: implications for ablation of atrial fibrillation (abstract). Heart Rhythm. 2012;suppl.
  9. Lee G, Kumar S, Teh A, et al. Epicardial wave mapping in human long-lasting persistent AF. Rotors, complex wavefronts and disorganized activity (abstract). Heart Rhythm. 2012;suppl.
  10. Lin Y-J, Lo M-T, Lin C, et al. The role of rotor in maintaining non-paroxysmal atrial fibrillation: insight from the mapping and catheter ablation, substrate characteristics, and prevalence (abstract). Heart Rhythm. 2012.
  11. Narayan SM, Krummen DE, Rappel W-J. Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation. J Cardiovasc Electrophysiol. 2012;23:447-454.
  12. Narayan SM, Bode F, Karasik PL, Franz MR. Alternans of atrial action potentials as a precursor of atrial fibrillation. Circulation. 2002;106:1968-1973.
  13. Narayan SM, Franz MR. Quantifying fractionation and rate in human atrial fibrillation using monophasic action potentials: implications for substrate mapping. Europace. 2007;9:vi89-vi95.
  14. Narayan SM, Kazi D, Krummen DE, Rappel WJ. Repolarization and activation restitution near human pulmonary veins and atrial fibrillation initiation: a mechanism for the initiation of atrial fibrillation by premature beats. J Am Coll Cardiol. 2008;52:1222-1230.
  15. Narayan SM, Franz MR, Clopton P, et al. Repolarization alternans reveals vulnerability to human atrial fibrillation. Circulation. 2011;123:2922-2930.
 

  1. Lalani G, Schricker A, Gibson M, et al. Dynamic conduction slowing precedes human atrial fibrillation initiation: insights from bi-atrial basket mapping on transitions to atrial fibrillation. J Am Coll Cardiol. 2012;59:595-606.
  2. Teh AW, Kistler PM, Lee G, et al. Electroanatomic remodeling of the left atrium in paroxysmal and persistent atrial fibrillation patients without structural heart disease. J Cardiovasc Electrophysiol. 2012;23:232-238.
  3. Mahnkopf C, Badger TJ, Burgon NS, et al. Evaluation of the left atrial substrate in patients with lone atrial fibrillation using delayed-enhanced MRI: implications for disease progression and response to catheter ablation. Heart Rhythm. 2010;7:1475–1481.
  4. Zhao J, Huang W, Yao Y, et al. Electropathological substrate detection of persistent atrial fibrillation--a novel method to analyze unipolar electrograms of noncontact mapping. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:1471-1474.
  5. Narayan SM, Shivkumar K, Krummen DE, et al. Panoramic electrophysiological mapping but not individual electrogram morphology identifies sustaining sites for human atrial fibrillation (AF rotors and focal sources relate poorly to fractionated electrograms). Circ Arrhythm Electrophysiol. 2013.
  6. Narayan SM, Patel J, Mulpuru S, Krummen DE. Focal impulse and rotor modulation (FIRM) ablation of sustaining rotors abruptly terminates persistent atrial fibrillation to sinus rhythm with elimination on followup. Heart Rhythm. 2012;9:1436-1439.
  7. Haïssaguerre M, Lim KT, Jacquemet V, et al. Atrial fibrillatory cycle length: computer simulation and potential clinical importance. Europace. 2007;9(Suppl 6):vi64-70.
  8. Takahashi Y, O’Neill MD, Hocini M, et al. Characterization of electrograms associated with termination of chronic atrial fibrillation by catheter ablation. J Am Coll Cardiol. 2008;51:1003-1010.
  9. Jais P, Hocini M, Sanders P, et al. Long-term evaluation of atrial fibrillation ablation guided by noninducibility. Heart Rhythm. 2006;3:140-145.
  10. Narayan SM, Day J, Ellenbogen K, et al. Elimination of sources for human atrial fibrillation (focal impulse and rotor modulation, FIRM) organizes and acutely terminates AF prior to pulmonary vein isolation: a multicenter experience (abstract). Circulation. 2012.
  11. Oral H, Chugh A, Lemola K, et al. Noninducibility of atrial fibrillation as an end point of left atrial circumferential ablation for paroxysmal atrial fibrillation: A randomized study. Circulation. 2004;110:2797-2801.
  12. Narayan SM, Patel J, Mulpuru SK, Krummen DE. Focal impulse and rotor modulation (FIRM) of sustaining rotors abruptly terminates persistent atrial fibrillation to sinus rhythm with elimination on follow-up. Heart Rhythm. 2012;9:(in press).
  13. Oral H, Chugh A, Good E, et al. Radiofrequency catheter ablation of chronic atrial fibrillation guided by complex electrograms. Circulation. 2007;115:2606-2612.
  14. Oral H, Chugh A, Yoshida K, et al. A randomized assessment of the incremental role of ablation of complex fractionated atrial electrograms after antral pulmonary vein isolation for long-lasting persistent atrial fibrillation. J Am Coll Cardiol. 2009;53:782-789.
  15. Oral H, Pappone C, Chugh A, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med. 2006;354:934-941.
 

  1. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA. 2005;293:2634-2640.
  2. Narayan S, Shivkumar K, Krummen D, et al. Panoramic electrophysiological mapping but not electrogram morphology identifies stable sources for human atrial fibrillation. 2012. Submitted.
  3. Kalifa J, Tanaka K, Zaitsev AV, et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation. 2006;113:626-633.
  4. Klos M, Calvo D, Yamazaki M, et al. Atrial septopulmonary bundle of the posterior left atrium provides a substrate for atrial fibrillation initiation in a model of vagally mediated pulmonary vein tachycardia of the structurally normal heart. Circ Arrhythm Electrophysiol. 2008;1:175-183.
  5. Oakes RS, Badger TJ, Kholmovski EG, et al. Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation. 2009;119:1758-1767.
  6. Krummen DE, Bayer JD, Ho J, et al. Mechanisms for human atrial fibrillation initiation: clinical and computational studies of repolarization restitution and activation latency. Circ Arrhythm Electrophysiol. 2012.
  7. Narayan SM, Franz MR, Clopton P, et al. Repolarization alternans reveals vulnerability to human atrial fibrillation. Circulation. 2011;123:2922-2930.
  8. Lin J, Scherlag BJ, Zhou J, et al. Autonomic mechanism to explain complex fractionated atrial electrograms (CFAE). J Cardiovasc Electrophysiol. 2007;18:1197-1205.
  9. Narayan SM, Wright M, Derval N, et al. Classifying fractionated electrograms in human atrial fibrillation using monophasic action potentials and activation mapping: evidence for localized drivers, rate acceleration, and nonlocal signal etiologies. Heart Rhythm. 2011;8:244-253.