Color Atlas and Synopsis of Electrophysiology, 1st Ed.

36. APPROACHES TO ABLATION OF ATRIAL FIBRILLATION: FRACTIONATED ELECTROGRAMS

Koonlawee Nademanee, MD

CASE PRESENTATION

A 74-year-old man with a history of hypertension and a transient ischemic attack has paroxysmal atrial fibrillation (AF) for 42 months. He has failed propafenone, sotalol, and dronedarone. His ejection fraction (EF) was 70%, and his left atrial (LA) diameter was 44 mm. AF was induced in the EP lab by isoproterenol infusion (Figure 36-1A) which precipitated spontaneous AF initiated by a premature atrial capture emanating from the right superior pulmonary vein (RSPV). Figure 36-1B shows the LA complex fractionated atrial electrogram (CFAE) map in PA and AP views on the electroanatomic map. The colors display the areas according to the cycle lengths of the CFAEs. The map shows the CFAEs area localized around the left inferior pulmonary vein (LIPV), antrum of the RSPV, and septum as shown in the red color. The rest of the LA was relatively organized and being activated with a relatively much longer cycle length. In this case, the RSPV has the shortest cycle length of CFAEs (<100 ms) and serve as the prime target for ablation (Figure 36-1C). Note that there were also distinct differences between the cycle lengths of the electrograms recorded from RIPV antrum than those recorded from coronary sinus. Ablations at these sites progressively lengthened tachycardia cycle length and eventually reverted AF to sinus rhythm (SR) (Figure 36-1D). After ablation, both a high dose of isoproterenol infusion and rapid burst pacing could not induce any atrial tachyarrhythmias (Figure 36-1E). His procedure lasted only 86 minutes, and fluoroscopic time lasted only 4 minutes and 6 seconds. The patient remained symptom- and arrhythmia-free during the long-term follow-up.

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FIGURE 36-1 (A) PAC from the right superior pulmonary vein (RSPV) that triggered AF. Once AF was sustained, a CFAE map was performed as shown in B. The LA map was created during AF. The map displays CFAE areas with respect to the shortest cycle length of the fractionated electrogram. Red areas have the shortest cycle length, and in this patient the RSPV, septum, and antrum of the left inferior pulmonary vein (LIPV) had the shortest cycle length (<100 ms). (C) The electrograms recorded from the LIPV as shown in the inset (arrow); note the much shorter cycle length at this site compared to the electrograms recorded from the coronary sinus. The red dots are the RF application points. Ablations were performed in these areas and rendered AF termination (D) and noninducible tachyarrhythmias with a high dose isoproterenol infusion (20 μg/min E).

ABLATION THERAPY FOR ATRIAL FIBRILLATION

The watershed observation by Haissguerre et al that PVs are an important source of triggering foci for paroxysmal AF has drawn electrophysiologists’ attention to the PVs as important target sites for AF ablation1. Although the initial approach was to focally ablate the culprit PV that was identified as the triggering site initiating AF,1,2 this approach quickly was out of vogue because numerous limitations: (1) difficulty of mapping the triggering focus due to a paucity of spontaneous AF coupling and time consuming because inducing the triggering arrhythmia often required multiple provocation and was quite inconsistent; (2) a daunting task of mapping multiple triggering foci; (3) multiple cardioversions were often needed for those whose AF became persistent. The strategy then changed to attempt to isolate the electrical connections of all four veins from the LA muscle.3-5 Various techniques were utilized to achieve electrical isolation of PVs: segmental isolation introduced by Haissaguerre and his colleagues,3 PV isolation at the antrum at the atrium-venous junction,4 or electroanatomical mapping and circumferential PV ablation.5

However, a total isolation of all four PVs poses a risk of PV stenosis. Furthermore, this strategy assumes that PVs are virtually the primary source of triggers or the perpetuator of AF, and thus all AF patients were essentially treated the same way—guided by anatomical scheme rather than electrophysiological mapping. As a result, electrical isolation of PVs has a variable rate of success in treating patients with all types of AF.6,7

We have utilized a different approach in ablating AF by using electroanatomical mapping of a substrate that perpetuates AF through identification of areas that have CFAEs during AF.

CHARACTERISTICS OF ATRIAL ELECTROGRAMS DURING ATRIAL FIBRILLATION

When one maps both atria during AF, one finds that there are three types of atrial electrogram characteristics8-10 (Figure 36-2). Atrial electrograms during sustained AF have three distinct patterns: single potential, double potential, and complex fractionated potential (CFAE). There are significant differences in these atrial electrograms during AF with respect to their cycle lengths and patterns and their regional distribution. Interestingly, areas that harbor CFAE with a very short cycle length have proclivity to localize and cluster in specific areas of the atria and do not meander; in other words, these atrial electrograms exhibit surprisingly remarkable temporal and spatial stability. These CFAE areas represent the AF substrate sites and become important target sites for AF ablation. By ablating such areas that have persistent CFAEs recording, one eliminates AF and usually renders AF noninducible. With this observation, CFAE mapping has become a novel approach for guiding a successful ablation of AF substrate with excellent long-term outcomes.

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FIGURE 36-2 Complex fractionated atrial electrograms (CFAEs) are composed of two deflections or more and/or have a perturbation of the baseline with continuous deflections from a prolonged activation complex with a very short cycle length. This figure shows an electroanatomical map of the LA in the LAO-oblique view, displaying the shortest cycle length of the recording sites in the span of 2.5 seconds ranging from 50 to 120 ms. The site from anterior aspect of the LA around the antrum of right superior pulmonary veins (arrow) had continuous low voltage fractionated atrial electrograms with the shortest cycle length of 54 ms (Map 1-2). In contrast, electrograms recorded from the coronary sinus (Ref 1-2) showing varying three types of electrograms in the same short time span; note that CFAE of this site are fleeting, sandwiching between a double potential electrogram and a single potential; note also that the cycle length of this recording site is much longer than that of the Map 1-2 recording site. CFAE recorded from Map 1-2 is an ideal target for ablation.

CFAEs are usually low voltage multiple potential signals between 0.05 and 0.15 mV. CFAEs are defined as follows: (1) atrial electrograms that have fractionated electrograms composed of two deflections or more, and/or have a perturbation of the baseline with continuous deflection of a prolonged activation complex (Figure 36-2). (2) Atrial electrograms with a very short cycle length (<120 ms) with or without multiple potential; however, when compared to the rest of the atria, this site has the shortest cycle length (Figure 36-3) that drives the rest of the atria. These CFAEs, as shown in Figure 36-3, are also important targets for ablations.

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FIGURE 36-3 An example of CFAE that has very short cycle length. It is much shorter than those recorded from the rest of atria, despite having no multiple prolonged potentials.

ELECTROPHYSIOLOGIC MECHANISMS UNDERLYING CFAEs

The elegant study by Konings et al showed that the complex, multiple component fractionated electrical potentials observed during intraoperative mapping of human AF were found mostly in the areas of slow conduction and/or pivot points where the wavelets turn around the end of the arch of the functional block.8,9 Thus, such areas of fractionated electrical recordings during AF represent either continuous reentry of the fibrillatory waves into the same area or the overlap between different wavelets entering the same area at different times.

Kalifa et al12 identified a key relationship between areas of dominant frequency and areas of fractionation in sheep. The investigators were able to localize areas with regular, fast, spatio-temporally organized activity and map the regions around them. Waves propagating from these areas were found to break and change direction recurrently at a boundary zone and demonstrate fractionation of local electrograms. Their findings suggested that one of the possible electrophysiologic mechanisms for AF relating to the hypothesis that high-frequency reentry at the boundary zones is responsible for the fractionation.

The most prominent theory underlying the occurrence of CFAE involves the complex interplay of the intrinsic cardiac nervous system on atrial tissues. The cardiac ganglionic plexi (GP) are a collection of autonomic nervous tissues with afferent and efferent sympathetic and parasympathetic fibers.13,14 Six major GPs that may exert influence on the atria are the superior LA, the posterolateral LA, the posteromedial LA, the anterior descending LA, the posterior right atrium (RA), and the superior RA. In animal models, the stimulation of parasympathetic fibers within the GP has been shown to decrease atrial effective refractory periods and allow AF to perpetuate. Quan KJ et al13 showed that electrical stimulation of cardiac ganglia near the PV orifices significantly shortened the atrial refractoriness close to the site of the stimulation and that the effects diminished at >2 cm away from this site. This raises the possibility that neurotransmitter release ie, acetylcholine, at preganglionic, and/or postganglionic terminal may contribute to the genesis of CFAEs and may play role in the differences of CFAEs regional distribution in the atria during AF. Indeed, Scherlag et al14 have demonstrated quite convincingly that in the areas of the LA where the GPs are identified by high frequency stimulation, CFAEs were almost always recorded after the high frequency stimulation initiated AF. They suggest that a marked shortening of action potential duration and formation of early repolarization caused ectopic beats, initiating AF that was sustained by the marked shortening of the refractory period. Ongoing research has identified a close relationship between the location of CFAE and the GP in animal models.15-18 CFAE-targeted ablation may provide a surrogate for modification of the GP if this relationship can be confirmed in humans. Certainly, ablation in areas that have resulted in a vagal response has shown excellent results in the treatment of AF.

It is possible that all of the above electrophysiologic changes are the underlying causes of CFAE. However, regardless of the mechanism underlying CFAEs, it is very likely that CFAE areas represent substrate areas that perpetuate AF.

REGIONAL DISTRIBUTION OF CFAE

The regions that harbor CFAE are not symmetrically located within the atria, and the distribution of CFAE in the right and left atria is vastly different from one area to another but can be predictably sought in certain places during mapping.10,11 CFAE are surprisingly stationary and exhibit relative spatial and temporal stability; thus, one can perform point-to-point mapping of these CFAE areas and associate them into an electroanatomical map. The following key areas have demonstrated a predominance of CFAE within our cohort: the proximal coronary sinus; the superior vena cava-RA junction; the septal wall anterior to the right superior and inferior PVs; the anterior wall medial to the LA appendage; the area between the LA appendage and left superior PV; and the posterosuperior wall medial to the left superior PV (Figure 36-3). Typically, patients with persistent or long-lasting AF have greater numbers and locations of sites with CFAE than those with paroxysmal AF.10

CFAE MAPPING TO GUIDE SUBSTRATE ABLATION

Mapping is always performed during AF by point-to-point mapping, although detailed mapping of the LA, coronary sinus, and, occasionally, RA is required. The spatial and temporal stability of CFAE allows the precise localization of these electrograms. A map with a minimum of 100 data points is usually created, especially in high-density areas commonly known to have CFAE. Additionally, we usually create a detailed map of the proximal coronary sinus, and occasionally the RA. We identify locations with stable electrograms, and these are “tagged” to create targets for ablation. Areas with fleeting CFAE are not sought as primary targets. A highly reliable map allows for minimal use of fluoroscopy. We routinely use less than 10 minutes of fluoroscopic time during average procedure duration of approximately 120 minutes.

A customized software package to assist in the process of mapping (CFAE software module, CARTO, Biosense-Webster, Diamond Bar, CA, United States) was produced.19 The software analyzes data on atrial electrograms collected from the ablation catheter over a 2.5-second recording window and interprets it according to two variables: (1) shortest complex interval (SCL) in milliseconds, out of all intervals identified between consecutive CFAE complexes over the span of 2.5 ms; and (2) interval confidence level, the number of intervals identified between consecutive complexes identified as CFAE. The assumption is that the more complex intervals recorded during the signal recording time (2.5 ms), that is, the more repetitions in a given time duration, the more confident the categorization of CFAE. Information from these variables is projected on a three-dimensional electroanatomical shell according to a color-coded scale. This allows targeting and retargeting of areas of significant CFAE.

PROCEDURAL DETAILS

A decapolar catheter is placed in the coronary sinus for reference and pacing. A single transseptal puncture under hemodynamic and fluoroscopic guidance is used to access the LA. Patients who are not in AF at the onset of the procedure undergo an aggressive induction protocol utilizing intravenous isoproterenol up to 20 μg/min and adenosine injection at the dose of 24 mg. If AF was not initiated, then burst pacing is performed in the coronary sinus and atria at a lower limit of 1:1 capture or the shortest cycle length of 180 msec. AF is considered stable for mapping if it can be sustained for greater than 30 seconds.

We use an open-irrigation 3.5-mm tip ablation catheter with a large or extra-large curve (Thermacool F or J, Biosense-Webster) irrigating at 30 mL/min during lesion creation. Power settings are 35 to 50 watts throughout the atria except for the posterior wall (25-35 watts) and coronary sinus (10-30 watts). Careful power titration is required during radiofrequency (RF) to ensure complete lesion creation. RF duration is usually 10 to 60 seconds and is halted because of patient discomfort or elimination of CFAE. Because of occasional noise on the ablation catheter during RF, multiple short (15-30 seconds) applications may be used.

One of the most important aspects of CFAE ablation (and one of the most common challenges early in the learning curve of this technique) is to revisit areas that were initially ablated to ensure that there has been no recovery of electrical activity. If the patient remains in AF despite elimination of all visible CFAE, intravenous ibutilide (1 mg over 10 minutes; may repeat once to a maximum of 2 mg) is used to increase the cycle length of the arrhythmia in “nondriver” atrial tissue and highlight the remaining areas of greatest significance (eg, CFAE associated with perpetuating AF). Often during CFAE-targeted AF ablation, the arrhythmia evolves into an atrial tachyarrhythmia (AT). Using the CS catheter as a reference, the AT is subsequently mapped and ablated. Most often the sites of origin of the AT are at the same locations as the CFAE, which were targeted during the initial part of the procedure. The end points employed are either termination of AF to SR (and if the presenting rhythm was paroxysmal AF, it must not be reinducible). or elimination of all CFAE. Occasionally, a patient will remain in AF or AT after an extensive ablation eliminating all CFAE, despite the use of ibutilide. In this small group of patients, an external cardioversion is required.

It is important to emphasize that the tachycardia cycle length is almost always progressively lengthening before the termination. If there is no change in the tachycardia cycle length, the ablation may not be effective, and one must reevaluate to determine if the RF power is delivered adequately or if remapping of the CFAEs is warranted.

CLINICAL OUTCOMES

The effectiveness of CFAE ablation for treatment of AF is highlighted in our study of high-risk patients with AF.20 Our study involved screening 2356 high-risk AF patients similar to those in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial population. Patients were at least 65 years old or had at least one or more risk factors for stroke, including hypertension, diabetes, structural heart diseases (coronary artery disease, valvular disease, cardiomyopathy, etc), a prior history of stroke or transient ischemic attack, congestive heart failure, or a left ventricular ejection fraction of <40%. We excluded patients with chronic alcoholism, recent myocardial infarction within one month of the study, significant debilitating diseases or terminal disease, and those with documented LA thrombus. After the screening of these patients for catheter ablation, we enrolled 771 patients with symptomatic refractory AF who had a high risk for stroke and, similar to those patients studied in the AFFIRM trial, were candidates for ablation.

Of the 771 patients, 674 underwent catheter ablations for AF; 39 were lost to follow-up within the three-month period after the ablation and were excluded from the study. Of the 97 patients who were not treated, 27 were excluded due to a LA thrombus and the other 70 patients declined the procedure. A total of 1065 ablations were performed on our 635 patients. There were 329 patients (52%) who underwent one procedure, 204 patients (32%) who required two procedures, 80 patients (12.6%) who required the procedure three times, and only 22 patients (3%) who required four procedures.

MAINTAINING SINUS RHYTHM AFTER CATHETER ABLATION

After a mean follow-up period of 836 ± 605 days, 517 were in SR (81.4%). AF ablations are significantly more effective in maintaining SR in patients with paroxysmal AF (226 of 254 patients [90%]) and persistent AF (124 of 146 patients [86%]) compared with those with permanent AF (167 of 235 patients [70%]). Of the 517 patients who remained in SR, only 68 patients (13%) required antiarrhythmic agents to maintain SR (48 amiodarone, 19 sotalol, and 1 dofetilide).

MORTALITY REDUCTION AFTER MAINTAINING SINUS RHYTHM FOLLOWING ABLATION

Interestingly, maintaining SR was associated with improved survival rate compared to those whose AF ablation failed to restore SR (P <0.0001). Over the follow-up period, there were 29 deaths: 15 patients who remained in SR and 14 who remained in AF died. Patients whose AF ablation was effective in maintaining SR had a much lower 5-year mortality rate (8%) than those with recurrent AF after the ablation (36%; P <0.0001) (Figure 36-4). It is possible that patients whose AF ablation failed to restore SR had more advanced heart disease or unrecognized risk factors that prevented them from maintaining SR and unfavorably influenced their overall survival. However, with the exception of the LA size and duration of AF, which were greater in patients who did not respond to AF ablation, there were no differences in terms of baseline patient characteristics, including EF. Multivariate analysis and Cox regression analysis convincingly show SR to be an independent predictor of a favorable prognosis, whereas EF, hypertension, and female gender had little effect. Sinus rhythm is an independent predictor of increased survival. Patients who maintained SR regardless of baseline EF had a lower mortality rate than their counterparts on the same corresponding EF stratum (Figure 36-5).

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FIGURE 36-4 Kaplan-Meir curve demonstrating improved survival in patients who remained in sinus rhythm from all-cause mortality compared to patients who remained in AF.

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FIGURE 36-5 Multiple overlay Kaplan-Meir survival curves among four strata of patients: (1) patients with an EF >40% and NSR (orange circle); (2) patients with an EF ≤40% and NSR (green circle); (3) patients with an EF >40% and AF (magenta circle); and (4) patients with an EF ≤40% and AF (blue circle).

The reason that patients who had a lower EF (<40%) but maintained SR fared better is probably the significant recovery of their ventricular function after restoring SR. The average EF increased from a mean of 31% prior to ablation to 41% following successful ablation (P <0.001). In contrast, patients who had recurrent AF after ablation had no change in their EF (Figure 36-6). Our data dovetail nicely with the findings of Hsu et al21 and Gentlesk et al22 that many AF patients with a depressed baseline EF show improvement in their EF after SR has been restored with a successful AF ablation.

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FIGURE 36-6 Comparison of individual changes of EF before and after ablation: Normal sinus rhythm (NSR) patients after ablation VS. AF patients after ablation: Pre = preablation and Post = 6-12 months postablation.

RELATION BETWEEN DISCONTINUATION OF ANTICOAGULATION THERAPY AND BLEEDING, STROKE, AND EMBOLIC INCIDENCE

Warfarin theray was discontinued in 434 patients (72.7%) whose AF was maintained after catheter ablation. Eleven patients experienced a major stroke or TIA. In the patients who discontinued warfarin, three patients developed a major stroke and two patients had a TIA compared with six patients in the group who required ongoing anticoagulation (five ischemic strokes and one fatal intracranial hemorrhage). The Kaplan-Meier curves for stroke rate are shown in Figure 35-7. The 5-year stroke rate was 3% in the group of patients who were off warfarin compared with 23% in the group of patients who remained in AF and continued taking warfarin (P = 0.004).

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FIGURE 36-7 Comparison of stroke-free survival between the two groups of patients: those who were on Coumadin (green) and those who were not (red).

PROCEDURE COMPLICATIONS

Five patients (0.9%) suffered from cerebrovascular accident (CVA). Incidentally, two of the five CVAs occurred 24 to 48 hours after the procedure. Hemopericardium occurred in seven patients (1.4%); one of these seven patients required cardiovascular surgical repair of the perforation of the LA at the ablation site, while the remaining six patients were treated successfully with pericardiocentesis. Nine patients developed major vascular complications at the groin sites (seven pseudoanerysm and two atrioventricular fistulas). Two patients developed atrioventricular block and required permanent pacemaker implantation. Three patients had a transient pulmonary edema after the procedure.

OTHER STUDIES AND CONTROVERSY

Our introduction of CFAE mapping to guide AF ablation, as an alternative to anatomical approach of PVI, spurred other investigators to follow our approach. However, our results were not fully reproduced by others.23-25 While it is unclear what exactly the factors are underlying the differences in both acute and long-term outcomes between our studies and others, it seems likely that one or more of the following key variables may help explain the differences between these studies26:

• RA ablation. Other investigators often did not map and ablate the RA. We found that 15% of our patients required RA ablation; the common sites are right postero-septum, cavotricuspid isthmus, tricuspid annulus, and, rarely, posterior wall of the RA and SVC-RA junction.

• Power and duration of RF energy applications. Our power of RF applications is significantly higher than those of others. We use RF power up to 50 watts over the anterior and septal wall and 30 to 40 watts in the posterior wall that is not close to the esophagus but titrates down to about 20 to 30 watts in the areas close to the esophagus.

• Ablation endpoint. Perhaps this variable is the most significant factor influencing the differences among these studies. CFAE are low voltage atrial signals usually ranging from 0.05 to 0.25 mV, and the areas with the very low voltage signals (between 0.05 and 0.1 mV) are often the most desirable. By contrast, other investigators defined successful lesion creation as a voltage reduction to <0.1 mV or decreased by <80%. This single factor may explain why the investigators did not have a high success rate of acute termination. In our experience, the ablation sites where AF terminated are often the sites that we had applied RF before, and often the voltage of atrial signals at these successful sites were in the range of 0.5 to 0.8 mV.

• Procedure endpoint. The procedure endpoint in our study is SR and/or complete elimination of CFAE target sites. We deliberately attempt to ablate all “new” arrhythmias including pleomorphic forms of atrial tachyarrhythmias whereas others often did not and elected to merely perform cardioversion to convert the arrhythmias to SR.

• Comprehensive mapping. Lastly, the electroanatomic map for CFAE should have high density of evenly spaced mapping points. It was unclear whether other investigators committed to detailed mapping of the CFAE; but there is no question that the key to the success of AF ablation guided by CFAE must have all areas of the atria and coronary sinus explored.

CONCLUSIONS

The above discussion and data of AF ablation guided by CFAE mapping are in contrast with previous studies in AF ablation that included largely young patients with paroxysmal AF population and show that our ablation techniques have greater benefit for the elderly and high risk populations with structural heart disease. Clearly, one must wait for more studies before recommending catheter ablation as the first line therapy for all high-risk AF patients. In the meantime, it is safe to say that catheter-based ablative approach is a promising modality for many symptomatic AF patients and that it has great potential to become the mainstay of AF treatment.

Finally, one must recognize that AF ablation, regardless of the technique, is a challenging task that requires operator skills in manipulating catheters in the atrial chambers, in understanding all facets of clinical electrophysiology, and in early recognition and treating procedure-related complications. Many of these skills could be achieved by proper training and hands-on experience after exposure to an adequate number of procedures. Advances in technology and development of new tools such as robotic navigation of catheters are being introduced at an impressive pace and will undoubtedly help electrophysiologists become more proficient in these tasks. Similarly, it is imperative that AF ablation procedures be done in centers that are well resourced with an advanced electrophysiology mapping system and ancillary equipment along with an experienced team to ensure the best possible outcome for patients.

REFERENCES

  1. Haissaguerre 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(10):659-666.

  2. Chen SA, Hsieh MH, Tai CT, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation. 1999;100: 1879-1886.

  3. Haïssaguerre M, Shah DC, Jaïs P, et al. Electrophysiological breakthroughs from the left atrium to the pulmonary veins. Circulation. 2000;102:2463-2465.

  4. Marrouch NF, Dresing T, Cole C, et al. Circular mapping and ablation of the pulmonary vein for treatment of atrial fibrillation. J Am Coll Cardiol. 2002;40:464-474.

  5. Pappone C, Oreto G, Lamberti F, et al. Catheter ablation of paroxysmal atrial fibrillation using a 3D mapping system. Circulation. 1999;100:1203-1208.

  6. 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. Heart Rhythm. 2012;9:632-696.

  7. Cappato R, Calkins H, Chen S, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation. 2005;111:1100-1105.

  8. Konings KTS, Kirchhof CJHJ, Smeets JRLM, et al. High-density mapping of electrically induced atrial fibrillation in humans. Circulation. 1994;89:1665-1680.

  9. Konings KTS, Smeets JLRM, Penn OC, et al. Configuration of unipolar atrial electrograms during electrically induced atrial fibrillation in humans. Circulation. 1997;95:1231-1241.

 10. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of electrophysiologic substrate. J Am Coll Cardiol. 2004;43:2044-2053.

 11. Jaïs P, Haïssaguerre M, Shah DC, et al. Regional disparities of endocardial atrial activation in paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 1996;19(pt 2):1998-2003.

 12. 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.

 13. Quan KJ, Lee JH, Van Hare GF, Biblo LA, Mackall, JA Carlson MD. Identification and characterization of atrioventricular parasympathetic innervation in humans. J Cardiovasc Electrophysiol. 2002;13:735-739.

 14. Scherlag BJ, Nakagawa H, Jackman WM, et al. Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. J Interv Card Electrophysiol. 2005:13:37-42.

 15. Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247:289-298.

 16. Pauza DH, Skripka V, Pauziene N, Stropus R. Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. Anat Rec. 2000;259:353-382.

 17. Scherlag BJ, Yamanashi W, Patel U, et al. Autonomically induced conversion of pulmonary vein focal firing into atrial fibrillation. J Am Coll Cardiol. 2005;45:1878-1886.

 18. Patterson E, Po SS, Scherlag BJ, et al. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm. 2005;2:624-631.

 19. Nademanee K, Schwab M, Porath J, Abbo R. How to perform electrogram guided atrial fibrillation ablation. Heart Rhythm. 2006;3:981-984.

 20. Nademanee K, Schwab MC, Kosar EM, et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol. 2008;51:843-849.

 21. Hsu LF, Jais P. Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med. 2004;351:2373-2383.

 22. Gentlesk PJ, Sauer WH, Gerstenfeld EP, et al. Reversal of the left ventricular dysfunction following ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2007; 18:9-14.

 23. Oral H, Chugh A, Good E, et al. Radiofrequency catheter ablation of chronic atrial fibrillation guided by complex electrograms. Circulation. 2007;115:2606-2612.

 24. Schmitt C, Estner H, Hecher B, et al. Radiofrequency ablation of complex fractionated atrial electrograms (CFAE): preferential sites of acute termination and regularization in paroxysmal and persistent atrial fibrillation. J Cardiovasc Electrophysiol. 2007;18:1039-1046.

 25. Verma A, Sanders P, Champagne J, et al. Selective complex fractionated atrial electrograms targeting for atrial fibrillation study (SELECT AF) a multicenter, randomized trial. Circ Arrhythm Electrophysiol. 2014;7(1):55-56.

 26. Nademanee K. Trials and travails of electrogram-guided ablation of chronic atrial fibrillation. Circulation. 2007;115:2592-2594.