1. New targets of AF ablation – CFAE and GPs Helmut Pürerfellner Public Hospital Elisabethinen, Academic Teaching Center Linz, Austria

2. Ablation strategy Focal (within PV) Segmental ostial Circumferential atrial Additional lines Substrate mapping (CAFE, DF) Ganglionated plexus (GP)

3. Lecture outline AF mechanisms Definition of complex fractionated atrial electrograms (CFAE) Mechanisms underlying CFAE Identification of CFAE Automated detection Conclusions

4. Mapping of human AF Atrial electrograms during sustained AF: single/double/complex fractionated potentials Localized to specific sites with remarkable temporal and spatial stability CFAE may represent AF substrate sites and are targets for AF ablation

5. Definition of CFAEs Atrial electrograms that are fractionated and composed of ≥2 deflections ± perturbation of the baseline with continuous deflections from a prolonged activation complex Atrial electrograms with a very short cycle length (≤120ms) ± multiple potentials when compared with atrial cycle length from other parts of the atria

6. Identification of CFAEs Visual inspection: subjective judgement, interobserver variability Automated detection: objective

7. Visual inspection of CFAEs

8. Visual inspection of CFAEs – Variable clinical results Nademanee et al (JACC 2004): 91% success at 1 year (PAF and CAF) Oral et al (Circulation 2007): 57% success at 13 months (only CAF) Verma et al (JCE 2007): 83% success at 13 months (PAF and CAF vs 72% control group PVAI only) Takahashi et al (JACC 2008): 90% success at 14 months (only CAF, combining with PVI and lines)

9. Characterization of Electrograms associated with termination of CAF by catheter ablation Takahashi et al, JACC 2008;51:1003-1010

10. Characterization of Electrograms associated with termination of CAF by catheter ablation Takahashi et al, JACC 2008;51:1003-1010

11. Characterization of Electrograms associated with termination of CAF by catheter ablation Takahashi et al, JACC 2008;51:1003-1010

12. Characterization of Electrograms associated with termination of CAF by catheter ablation Takahashi et al, JACC 2008;51:1003-1010

13. Automated detection of CFAEs – Why? Very low amplitude (0,06-0,25mV) Over a larger area: determination of exact boundaries Very short CL: determination of CL of a local EGM Improvement in detection/ quantification/regionalization Consistent definition between centers

14. Classification of Fibrillatory Electrograms* NAE CFAE Complex Fractionated Atrial Electrograms Distinct Fractionated Electrograms Continuous Fractionated Electrical Activity Normal Atrial Electrograms *MAPPING OF COMPLEX FRACTIONATED ATRIAL ELECTROGRAMS (CFAE) USING THE CARTO® XP SYSTEM T De Potter, MD and M Duytschaever, MD,PhD

15. Automated detection of CFAEs – CARTO, Biosense Webster Algorithm: 1. All peaks of bipolar deflections exceeding ±0.05mV are identified and tagged white (0.05-0.15 mV) or purple (>0.15mV) 2. Intervals between 2 successive peaks of 0.05 to 0.15mV are determined 3. Number of intervals between 70 and 120ms during 2,5 sec recording period determined (referred as interval confidence level, ICL)

16. CFAE Software Operation A point is acquired capturing 2.5 seconds of electrogram data Electrograms captured are analyzed in 2 ways simultaneously using: Voltage Criteria Interval Criteria (cycle length) results are displayed on a C ARTO ® XP System map using the familiar color scheme and/or local confidence tags

17. Algorithm Basics Amplitude The Upper threshold is set to include only low amplitude deflections (avoid ventricular far field sensing, large amplitide atrial signal) The Lower Threshold is set to ignore baseline noise (avoid noise oversensing)

18. Algorithm Basics Duration –The Min threshold excludes deflections that belong to one complex (avoid overcounting of a single deflection) –The Max threshold excludes deflections that are too far apart

19. ICL Threshold

20. Automated CFAE detection (CARTO) Scherr et al, Heart Rhythm 2007

21. Automated CFAE detection (CARTO) Scherr et al, Heart Rhythm 2007

22. CFAE Maps Shortest Complex Interval (SCI): Displays the value of the shortest interval between two consecutive CFAE in the signal Interval Confidence Level (ICL): If there are two or more adjacent CFAE complexes in the signal, the ICL displays the number of CFAE intervals Average Complex Interval (ACI): Displays the average value for all CFAE complex intervals in the signal

23. Automated detection of CFAEs – Ensite NavX, St. Jude Algorithm: measures the time between multiple discrete deflections (-dV/dT) in a local recording over a specified length of time (5 seconds) averages these interdeflection time intervals to calculate a mean CL of the local EGM during AF Mean CL projected onto LA anatomical shell colour coded CFEs exhibiting a mean CL <120ms

24. 1. All bipolar EGM peaks with a voltage amplitude ≥twice the maximal noise amplitude of the baseline 2. Refractory period from the previous detection set 3. CFE mean values obtained CFAEs detection steps– EnSite NavX, St. Jude

25. Refractory: limits double counting Width: limits detection to high frequency signals CFAEs detection steps– EnSite NavX, St. Jude 10-15 35-50 5sec

26. CFAE detection – EnSite NavX

27. Automated detection of CFAEs – Various aspects Minimal recording duration per site Temporal stability over AF ablation procedure

28. Consistency of CFAE – correlation between 1-7 vs 8 seconds Lin et al, Heart Rhythm 2008;5:406-412

29. Consistency of CFAE – FI variation between 1-7 vs 8 seconds Lin et al, Heart Rhythm 2008;5:406-412

30. Consistency of CFAE – Regional distribution 1 vs 8 seconds Lin et al, Heart Rhythm 2008;5:406-412

31. Consistency of CFAE – Comparison of FI and DF Lin et al, Heart Rhythm 2008;5:406-412

32. CFAE distribution and temporal stability Roux et al, JCE 2008

33. CFAE distribution and temporal stability Roux et al, JCE 2008

34. Mapping Mapping methodology is not changed Detailed baseline map is recommended (>80 points) in SR or AF Induction of AF is necessary CFAE areas may be further mapped and explored for more CFAE locations (dedicated CFAE mapping)

35. Endpoints for CFAE ablation Transformation from complex to discrete electrograms Complete elimination of areas with CFAE Slowing Organization in atrial tachycardias, atrial flutter Conversion to SR

36. Ablation of CFAE resulting in termination Courtesy of Dr Aichinger/Dr Pürerfellner, Linz, Austria

37. Is fractionation the AF substrate? (Active vs passive CFAEs) PRO: Identify critical pivot points (multiple wavelets) Unmask nearby rotors (focal sources) Identify enhanced GP activity (neural conduction) CONs: Occur during passive activation, CL dependency Just a marker of structural complexity (stationary, preferential sites) Noise

38. DF changes in PAF

39. DF changes in CAF

40. Conclusions 1 The contribution of electrogram based strategies to procedural success in AF ablation is an area of active investigation CFAEs with varying degrees of fractionation are found in >80% of LA endocardial/ epicardial locations during ongoing AF CFAE can be quantified by automated detection algorithms There is considerable CFAE variation which is critically dependent on the degree of fractionation and on the recording duration

41. Conclusions 2 Sites with consistent and a high degree of fractionation exhibit continuous activation which may define a site actively involved in the fibrillatory process (ablation target!) Automated detection of CFAE may therefore provide a widely applicable tool including an electrophysiological endpoint for more extensive ablations targeting the AF substrate However, there is still a a paucity of randomized trials and particularly of multicenter trials Further studies are clearly needed

42. « I will follow that system of regimen which, according to my ability and judgement, I consider for the benefit of my patients, and abstain from whatever is deleterious and mischievous. » Primum non nocere

44. Ablation strategy Focal (within PV) Segmental ostial Circumferential atrial Additional lines Substrate mapping (CAFE, DF) Ganglionated plexus (GP)

45. Programmed electrical nerve stimulation (PENS) and GP ablation Requires high rates and strengths of stimultion (appr. 10-15 times more than PES) Distal tip of map/ablation catheter deivering typically 1200 bpm (20Hz) with a pulse width of 10ms at 5 to 15 V High frequency stimulation (HFS) during SR at GP areas induces AFib (by local release of Acetylcholine) and CAFEs HFS during AFib induces vagal response (AV block and hypotension) within 10 sec Ablation directly over GP area infrequently causes symptoms HFS after ablation fails to reinduce vagal response (eliminates afferent response)

46. HFS

47. GP ablation Nakagawa et al, Heart Rhythm 2006

48. GP ablation

49. Future role: unclear Adjunct to conventional ablation strategies ?