Substrate Ablation (CAFE) A Promising or Vanishing Technique Walid I. Saliba, M.D. Director, Atrial Fibrillation Center Section of Pacing and Electrophysiology, Department of Cardiovascular Medicine THE CLEVELAND CLINIC FOUNDATION Cleveland, Ohio 1

Goal To confuse you

Natural History of AF Dual Substrate Model Ablation of Triggers Modification of Substrate Persistent Sinus can be restored electrically or chemically Paroxysmal Self terminating AF episodes Permanent Sinus cannot be maintained Atrial remodeling: ↓Refractory Period ↓ Conduction velocity Favors Arrhythmia “AF begets AF” Trigger initiation Substrate maintenance

Alternative Strategies More Ablation Where? Why? How much more? CAFE Dominant Frequency Ganglionic Plexi Stepwise/Tailored AF Nest SVC / CS / Septum / Crista LAA, LoM Flutter? CTI Lines, circles … Primary therapy Adjunctive therapy to PVI

What are CAFÉ’s EGMs with CL < 120 ms EGMs with continuous electrical activity EGMs with low amplitude and more than 2 deflections EGMs with CL shorter than in the CS or LAA

Mechanisms Underlying CAFE Pathological anisotropic conduction Slow conduction , Pivot and anchor points or Collision of the wavelets (Alessie 1996) Focal microreentry (Gardner/Alessie 1985) Wave break and fibrillatory conduction at the Borderzone of the mother rotors and areas of dominant frequencies. (Kalifa et al Circ 2006) Calcium transient triggering activities from hyperactive autonomic ganglionic plexi with shortening of the RP (Scherlag et al. 2004)

CAFÉ’s in Atrial Fibrillation Ablation Stand Alone Targets ( Nademaneee) Hybrid approach with PVI

Substrate-Guided Ablation: CAFÉ’s Nademanee et al, JACC 2004 Rationale Target key atrial regions responsible for perpetuating AF rather than targeting the triggers in the PV’s End Points Complete elimination of areas with CFAE’s Conversion of AF to SR

Substrate-Guided Ablation: CFAE Fractionated electrograms composed of 2 deflections or more and continuous deflection of baseline Atrial EGMs with very short CL <120 msec Nademanee et al, JACC 2004

Substrate-Guided Ablation: CFAE’s Median RF lesions: 64 60% patients had CFAEs clustered around PV’s 87% patients had CFAEs clustered around septum and roof, close to PVs. Nademanee et al, JACC 2004

Substrate-Guided Ablation: CFAE’s Only 121 pts (51 PAF, 64 Chronic AF) 91% of pts free of arrhythmia 23% required a 2nd. Ablation 13% on AAD Nademanee et al, JACC 2004

Stepwise Ablation Approach Haissaguerre et al. JCE 2005 Ablation of CAFÉ’s as part of a stepwise approach to achieve conversion to SR Rationale: Structures contributing to initiation and maintenance of AF are sequentially targeted With increasing ablation of left atrial structures, there is a cumulative increase in AFCL resulting in “AF termination” with each ablation step performed.

The Stepwise Ablation Approach Lasso Guided PV Isolation Roof Line Ablation Ablation of CS & Complex LA activities Mitral Isthmus Ablation Right Atrial / SVC Ablation Cardioversion

EGM Based Ablation Haissaguerre et al. J CardiovascElectrophysiol2005;16:1125-37

Stepwise Ablation Approach 60 pts with Non-PAF 87% (52) had AF termination during ablation (SR:7 ; AT:45) 60% success rate with a single procedure (40% required repeat ablation) 95% success rate with multiple procedures Sinus rhythm at 11±6 months f/u ,without AAD’s Good atrial transport function Haissaguerre et al., J C E, Vol. 16, pp. 1138 Nov 2005

Some Observations The greatest magnitude of prolongation of fibrillatory cycle length occurred during ablation at the PV-LA junction (Antrum) Coronary sinus Anterior LA Almost half of the residual atrial tahycardias originated these same sites.

RF ablation of CAFÉ’s in PV’s, LA and CS 100 pts with Chronic AF RF ablation of CAFÉ’s in PV’s, LA and CS End point: All CAFÉ’s eliminated or AF termination Circulation.2007;115:2606

CAFÉ’s 1 PV 46% CS 55% Septum/roof All CFAEs EGM: CL< 120 msec CL < CL n CS Fractionated and/or continuous electric activity 1 PV 46% CS 55% Septum/roof All

Results 33% in SR after a single ablation procedure Repeat ablation in 44% CAFÉ’s in antrum, PV tachycardia, Macroreentrant flutter and circuits…… 57% in SR at ~1 year follow up.

“The modest efficacy attained in this study despite extensive ablation of left atrial and coronary sinus CFAEs suggests either that CFAEs do not accurately identify sites that are critical to the maintenance of chronic AF or that ablation of CFAEs is not sufficient to eliminate the driving mechanisms of chronic AF in a large proportion of patients.”

Oral et al. J Am Coll Cardiol 2009;53:782–9) A Randomized Assessment of the Incremental Role of Ablation of Complex Fractionated Atrial Electrograms After Antral PV Isolation for Long-Lasting Persistent AF n=119 Group A: Termination with PVAI (n=19) Group B: No Termination→Cardioversion (n=50) Group C: No termination →CFAE* (n=50) *LA and CS for up to 2 hrs additional ablation Oral et al. J Am Coll Cardiol 2009;53:782–9)

CAFÉ: LA sites

A Randomized Assessment of the Incremental Role of Ablation of Complex Fractionated Atrial Electrograms After Antral PV Isolation for Long-Lasting Persistent AF After a single Ablation SR at 10 months Group A: Termination with PVAI (n=19) Group B: No Termination→Cardioversion (n=50) Group C: No termination →CFAE (n=50) 79% 36% P=0.84 34% Up to 2 h of additional ablation of CFAEs after PVAI does NOT appear to improve clinical outcomes in patients with long-lasting persistent AF. Oral et al. J Am Coll Cardiol 2009;53:782–9)

Repeat Ablation in 34 randomized patients. SR at 9 months Group B: No Termination→Cardioversion (n=50) Group C: No termination →CFAE (n=50) 68% P=0. 4 60% No Difference even with repeat ablation Oral et al. J Am Coll Cardiol 2009;53:782–9)

Methods Elayi et al. ;Heart Rhythm. 2008 5(12):1665 144 patients with permanent AF randomized to: Group I: Pulmonary Vein Antrum Isolation .(PVAI) n=48 Group II: Hybrid approach. (CFAE’s + PVAI) n=49 Initial defragmentation: targeting bi-atrial and CS CFAE, and started randomly in the right or left atrium followed by PVAI Group III: Large area circumferential ablation. (LACA) n=47 Targeting voltage reduction using electroanatomic mapping. (CARTO)

Defragmentation +PVAI Acute Results Group I Group II PVAI N=48 Defragmentation ONLY N=49 Defragmentation +PVAI P value SR 3 (6%) (0%) 2 (4%) NS AT 18 (38%) 1 (2%) 34 (70%) P<0.001 AF 27 (56%) 48 (98%) 13 (26%) P=0.01 Defragmentation alone did not have a significant effect on AF organization. Defragmentation as an adjunctive strategy to PVAI increases the rate of conversion from AF to organized arrhythmias.

Long Term Results Group I PVAI n=48 Group II CFAE+PVAI n=49 Mean follow-up (months) 11.4 ± 1.1 11.2 ± 1.2 Patients in sinus rhythm after a single procedure 42% 61% Patients in sinus rhythm after two procedures and with AAD if needed 83% 94% Better success rate when defragmentation was performed in conjunction with PVAI

LAA Cristal Terminalis CS Pre RF CS Post RF

Presenting for Ablation LSPV Post Antral Isolation Post CS & LA-CAFE AT Ablation

In high-burden paroxysmal/persistent AF, Substrate vs. Trigger Ablation for Reduction of AF: An International, Multicenter, Randomized Trial (STAR-AF) In high-burden paroxysmal/persistent AF, PVI+CAFE has the highest freedom from AF versus PVI or CAFE alone after one procedure. CAFE alone has the lowest procedure success rates with a higher incidence of repeat procedures Comparison of 3 strategies of AF ablation: (n=100 pts, 35% persistent) CFE ablation alone PVI ablation alone PVI+CFE hybrid ablation 74% 47% Freedom from AF 29% Verma et al, HRS LBT 2009

Outcomes of Different Ablation Approaches That Incorporated CFAE Ablation in Patients With Persistent AF N AF CAFÉ only PVI only PVI + CAFÉ Nademanee et al (2004) 121 P+C 91% Oketani et al (2008) 410 81% Verma et al (2007) 40 C 82% Star AF (2009) 100 29% 47% 74% Haissaguerre (2005) 60 95% * Orale at al.(2009) 50 60% Orale et al.(2006) 57% Meulet et al.(2007) 96 67% 66% Elayi et al. (2008) 97 83% 94% 60% 66% 83% After 1-2 ablations F/U ~1 year

Does CAFÉ substrate modification offer additional success? Conclusion Does CAFÉ substrate modification offer additional success? Different techniques, Different Operators, Different Skills, Different interpretations, Different endpoints, different experiences, different follow up’s: Can we generalize the information Can we trust the data: Is this Science? Significance of CAFÉ: Active vs Passive role? Is it just more Controlled Debulking? (CEDCA) I will let you draw your own conclusion

PV Antrum Isolation

Overlap of CFAE and PVI? Majority of ablated CFAE in tailored approach were in the LA Extensive “fixed” PV antral isolation includes most areas of CAFÉ.

Is More ablation better? More Ablation: Potential for More atrial Flutter More ablation: Compromise LA mechanical function More ablation: Interatrial / intraatrial dyssynchrony More ablation: More fluoro / More potential complications

OK, but what else can we ablate?… ﺒﻜﻔﻱ CAFE

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“AF-Nests” Spectral Mapping Guided AF Nests Ablation in Sinus Rhythm An Adjunctive Approach to PVAI and SVCI Well connected cells Loose cells, anisotropic conduction 40 Hz 50 Hz 120 Hz 200 Hz Segmented Spectrum Continuous Spectrum “AF-Nests”

AF NEST AF NEST Typical Sites Fibrillar Myocardium Pre RF CS AF NEST CS Post RF CS

157 Pts Prospectively Studied 91Pts > 2mo F/U Randomized AFN+PVAI+SVCI 45Pts PVAI+SVCI Recurrences PAF 11% Pers/Perm 20% Recurrences PAF 20% Pers/Perm 30%

Stepwise Ablation Approach Number of Patients Terminating with each Step of Ablation Cumulative benefit Progressive decrease in incremental benefit per stage after five stages of ablation beyond which further LA ablation is probably of no clinical benefit up to a limit