Treatment of Atrial Fibrillation by the Ablation of Localized Sources: CONFIRM Trial
Editor's Note: This Article of the Month is based on Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of Atrial Fibrillation by the Ablation of Localized Sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) Trial. J Am Coll Cardiol 2012;60:628-36.
Atrial fibrillation (AF) is the most common sustained arrhythmia1 and catheter ablation aiming to eliminate tissue critical to AF2 is found to be more effective than medications for its treatment.3-5 Nevertheless, many patients require multiple, lengthy, and costly ablation procedures that confer at least modest risk.2 AF ablation success is likely limited by the current available tools and lack of identification of AF sustenance mechanisms. There are currently two main competing hypotheses on mechanisms of AF sustenance:6 The multiple-wavelet hypothesis proposes that AF perpetuation is maintained by continuous annihilation and regeneration of randomly meandering electrical waves.7 Alternatively, the localized source hypothesis proposes that organized and fast reentrant circuits (rotors)8 or focal impulses9 are discrete and disorganize into fibrillatory waves at their periphery. However, until to date there has been only an indirect10,11 or no7 evidence to support localized sources in human AF. Narayan et al12 presents a study testing the hypothesis that human AF, even with a wide range of presentations, is sustained by localized sources whose targeted ablation improves outcomes.
Study design and enrollment. Ninety-two subjects with symptomatic AF undergoing 107 consecutive ablation procedures for standard indications were enrolled in the CONFIRM (Conventional Ablation With or Without Focal Impulse and Rotor Modulation) trial in five centers. Accordingly, consecutive cases were prospectively enrolled in a two-arm 1:2 case cohort design into the Focal Impulse and Rotor Modulation (FIRM) -guided group that received targeted ablation of sources (n=36), or the FIRM-blinded group, blinded to any clinical factors (n=71).
Electrophysiology study. Catheters were advanced from the femoral veins to the right atrium, coronary sinus and transseptally to the left atrium. A 64-pole basket catheter consisting of 8 electrodes along each one of 8 springy splines was advanced to record with a wide-field (panoramic) view unipolar and bipolar electrograms in the left atrium in all patients and in some patients also the right atrium. Digital electroanatomic atrial shells were created for clinical guidance of conventional ablation (not FIRM) using standard electroanatomical mapping systems. AF was induced in 28 patients presenting in sinus rhythm via pacing or isoproterenol.
Computational mapping of patient-specific AF mechanisms. Electrograms from the basket catheter were analyzed with a novel software system and used to identify intra-procedurally, in near real-time, mapped propagation patterns that were physiologically possible during AF. The FIRM maps of AF revealed electrical rotors defined as sequential isochrones around a center of rotation with waves emanating outwardly, or focal impulses defined by centrifugal activation isochrones from a point origin. Rotors and focal impulses showed limited spatial meandering and were considered AF sources only if consistent in multiple recordings over >10 min.
Ablation procedure. In FIRM-guided subjects, Radiofrequency ablation commenced to eliminate identified sources through a catheter maneuvered to the basket electrode overlying each source and radiofrequency energy was applied for 15 to 30 sec. The catheter was moved within the area indicated by FIRM maps to represent the center of rotation or focal impulse origin until AF terminated or ablation time at that source reached ≤10 min, whichever came first (typically <5 min per source). If AF terminated, attempts were made to reinitiate AF. If AF was successfully reinitiated, FIRM ablation was repeated for ≤3 sources. Conventional ablation was then performed. Conventional ablation, performed after FIRM ablation in the FIRM-guided group, and as sole therapy in the FIRM-blinded group, comprised wide area circumferential ablation to isolate the left and right pulmonary veins in pairs, with verification of pulmonary vein isolation using a Lasso mapping catheter. In cases of persistent AF, we also used a left atrial roof line. If AF persisted after completion of the ablation protocol in each group, cardioversion was performed.
Mechanisms. The mapping of the arrhythmia revealed sources in the form of electrical rotors (70%) and focal impulses (30%) in 98 of 101 cases of sustained AF. The AF sources, conserved for at least tens of minutes during mapping (FIRM-guided cases), were found widespread across locations in the left atrium (76%), including sites outside the pulmonary veins (PVs), posterior, inferior, roof and anterior regions, and in the right atrium (24%) including the inferolateral, posterior, and septal regions. There were a median of two sources in persistent or spontaneous AF as compared with a single source in paroxysmal or induced AF. The number of sources did not depend on age, historical duration of AF, or the number of prior conventional ablation procedures.
Ablation endpoint. FIRM ablation alone achieved the acute endpoint of AF termination or 10% slowing in 31 of 36 (86%) patients. The AF terminated in 20 of 36 cases (56%) with 4.3±6.3 min of FIRM ablation at the primary source (median 2.5 min). In the 11 of 36 cases in whom AF did not terminate, AF slowed by 33±12 ms (19±8%). Total FIRM ablation time (at all targeted sources) was 16.1±9.8 min. By comparison, in the FIRM-blinded group, the acute endpoint was achieved in 13 of 65 cases with sustained AF (20%) after 43.4±28.0 min (median 31.8 min) ablation (p<0.001 for both comparisons against FIRM-guided limb).
Follow-up. Follow-up was more rigorous in the FIRM-guided group than in the FIRM-blinded group through more common use of implantable ECG monitors in the former. Single procedure freedom from AF was higher for FIRM-guided than for FIRM-blinded cases (82.4% vs. 44.9%; p<0.001) after median 273 days. FIRM-guided therapy maintained its treatment benefit over FIRM-blinded therapy for first-time ablation cases as no FIRM-guided case recurred after ~7 months. Freedom from any atrial tachyarrhythmia after a single procedure was also higher in FIRM-guided than in FIRM-blinded cases (70.6% vs. 39.1%; p=0.003). Neither the total duration of ablation, the aggregate number, nor the type of adverse events differed between the two groups.
The authors conclude that human AF is typically caused by very few localized sources that cause disorganization in the remaining atria. Focal impulse and rotor modulation (FIRM) ablation to eliminate these sources was able to abruptly terminate or consistently slow persistent and paroxysmal AF in the vast majority of cases, and substantially improve long-term AF elimination over conventional ablation alone in this prospective case cohort study. The authors further assert that FIRM mapping may open the possibility for several patient-tailored therapies for AF in addition to ablation.
Despite remarkable progress in catheter ablation of AF, primarily based on elimination of PVs arrhythmogenicity, identification of drivers beyond the thoracic veins specifically in patients with persistent AF remains problematic. Both simulation and experimental studies in animal models have demonstrated that despite the spatiotemporal complexity of wave propagation during AF, measurable deterministic properties of high frequency sources, rotors and hierarchical distribution of dominant frequency (DF) as a consequence of fast rotors identified in the phase domain13,14 play a critical role in the perpetuation of fibrillation.8,15-18 However, these important mechanistic studies involved toxic voltage sensitive dyes and high density mapping ex-vivo and clinical utility of these seminal findings have been limited.
Thus with the much need to further improve the understanding and outcomes of catheter ablation of AF in patients, particularly persistent AF, the study by Narayan et al.12 is a timely contribution. In this study, the authors used a 64-electrode panoramic mapping catheter and an intra-procedural activation analysis system and showed for the first time that stable rotors and ectopic impulses are the drivers of both paroxysmal and persistent AF in the vast majority of patients. The targeting of those localized drivers by ablation has further improved acute and follow-up outcomes. The study therefore demonstrates that a panoramic mapping approach utilizing algorithms, primarily based on phase analysis of simultaneously recorded electrograms, for identification of activation patterns through a multichannel catheter, is an effective approach in studying and treating the individual and particular form of AF in different patients.
The work presented by Narayan et al. advances both the basic research and the clinical treatment of AF in humans. Based on the data presented, it is now strongly suggested that both paroxysmal and persistent AF are largely dependent on stable drivers. Because of the relativity low resolution of the mapping system and the inherent far-field contribution to the electrogarms recorded in this study, it is still somewhat uncertain whether, on one hand, the rotors seen are actually focal activity with a sequentially delayed detection, or, on the other hand, the focal discharges are not actually an endocardial representation of intramural reentries.19,20 Nevertheless, the ability to localize AF drivers is a major progress in the prospect of improving AF ablation outcomes. The slowing of the AF without termination by the ablation is however indicative of further efforts needed in ablation and treatment procedures. Notwithstanding the important limitations of the work and the challenges ahead, the authors should be commended for opening a new chapter in the study and treatment of AF. As is the case often, the utility, efficacy and wide adoption of this method will largely depend on further research and validation.
- 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;114:119-25.
- 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: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012;9:632-96.
- 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;293:2634-40.
- Oral H, Pappone C, Chugh A et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 2006;354:934-41.
- 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;303:333-40.
- Jalife J, Berenfeld O, Skanes A, Mandapati R. Mechanisms of atrial fibrillation: mother rotors or multiple daughter wavelets, or both? J Cardiovasc Electrophysiol 1998;9(8 Suppl):S2-S12.
- Allessie MA, de Groot NM, Houben RP et al. Electropathological substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: longitudinal dissociation. Circ Arrhythm Electrophysiol 2010;3:606-15.
- Mandapati R, Skanes A, Chen J, Berenfeld O, Jalife J. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. Circulation 2000;101:194-9.
- Sahadevan J, Ryu K, Peltz L et al. Epicardial Mapping of Chronic Atrial Fibrillation in Patients: Preliminary Observations. Circulation 2004;110:3293-9.
- Cuculich PS, Wang Y, Lindsay BD et al. Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. Circulation 2010;122:1364-72.
- Atienza F, Almendral J, Moreno J et al. Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: evidence for a reentrant mechanism. Circulation 2006;114:2434-42.
- Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of Atrial Fibrillation by the Ablation of Localized Sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) Trial. JACC 2012;60:628-36.
- Chen J, Mandapati R, Berenfeld O, Skanes AC, Gray RA, Jalife J. Dynamics of wavelets and their role in atrial fibrillation in the isolated sheep heart. Cardiovasc Res 2000;48:220-32.
- Warren M, Berenfeld O, Guha P et al. IK1 blockade reduces frequency, increases organization and terminates ventricular fibrillation in the guinea pig heart. PACE 24, 647. 2001. Abstract.
- Mansour M, Mandapati R, Berenfeld O, Chen J, Samie FH, Jalife J. Left-to-right gradient of atrial frequencies during acute atrial fibrillation in the isolated sheep heart. Circulation 2001;103:2631-6.
- Berenfeld O, Zaitsev AV, Mironov SF, Pertsov AM, Jalife J. Frequency-dependent breakdown of wave propagation into fibrillatory conduction across the pectinate muscle network in the isolated sheep right atrium. Circ Res 2002;90:1173-80.
- Zlochiver S, Yamazaki M, Kalifa J, Berenfeld O. Rotor meandering contributes to irregularity in electrograms during atrial fibrillation. Heart Rhythm 2008;5:846-54.
- 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;113:626-33.
- Tanaka K, Zlochiver S, Vikstrom KL et al. Spatial distribution of fibrosis governs fibrillation wave dynamics in the posterior left atrium during heart failure. Circ Res 2007;101:839-47.
- Berenfeld O, Oral H. The quest for rotors in atrial fibrillation: Different nets catch different fishes. Heart Rhythm 2012;9:1440-1.
Keywords: Activation Analysis, Atrial Fibrillation, Catheter Ablation, Coronary Sinus, Femoral Vein, Isoproterenol, Pulmonary Veins
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