The Future. Sanjiv M. Narayan, MD, PHD, FHRS, FRCP Professor of Medicine, University of California San Diego San Diego Veterans Affairs Medical Center

Transcription

1 The Future Sanjiv M. Narayan, MD, PHD, FHRS, FRCP Professor of Medicine, University of California San Diego San Diego Veterans Affairs Medical Center Disclosures: Funded by NIH (HL70529, HL83359, HL103800, SBIR) and Doris Duke Charitable Foundation grants to SMN. SMN is a co-inventor of IP owned by UC Regents and licensed to Topera. SMN holds equity in Topera. Topera has not sponsored any research, including that presented here. SMN: Medtronic, St Jude Medical, Biosense-Webster, Biotronik

2 Back to the Future

3 Determinants Ablation: The Future The Past Ablation Disease Mechanisms

4 Atrial Fibrillation From Observation back to Mechanism then into Therapy Oakes/Marrouche, Circ 2009 Spragg/Calkins, HR 2012 Predictive Modeling CABANA Survival Benefit? Ablation Narayan/Franz, Circ 2002 PREVENTION Substrates Stable Rotors, Focal Sources

5 Does One Predominant Mechanism Underlie Paroxysmal, Persistent and Longstanding Persistent AF? Mild Exertional Paroxysmal Chest AF Pressure Sudden Persistent Death AF Left Main Stenosis Distal Circumflex Stenosis Shivkumar, Ellenbogen, Hummel, Miller Steinberg. J Cardiovasc Electrophysiol 2012; 23(12):

6 Atrial Fibrillation The Observation. Mechanism? Mechanisms? 1+ Procedures (n=103) LA line, n=23 (22.3%) SVC, n=17 (16.5%) Other Foci, n=17 (16.5%) 67%. 5% still on drug 12.6% 2+ procedures STOP-AF (2013) Single Procedure RAAFT-2 (2012) MANTRA-PAF (2012) 1 Wilber, JAMA 2010; 303(4): , and FDA Review; 2 Morillo, RAAFT-2. HRS 2012 LBCT; Nielsen et al., MANTRA-PAF, New Engl J Med, 2012; Packer et al., STOP AF. JACC 2013

7 Back to the Future: AF Drivers in Classical Studies AF may be sustained by organized spiral waves (rotors) 2-6. Optical Mapping 4,5 Clinical local AF termination Tzou et al., JCE CONFIRM Unexpectedly, (2011):.. When AF rotors/sources [fibrillation] became typically sustained, human the reentry AF tended Focal Impulse to stabilize and to Rotor a small, Modulation single, relatively (FIRM) stable Multicenter reentrant Validation. Mechanism circuit. 1 to Therapy. 1 Schuessler, Cox, Boineau, et al. Circ Res 1992; 71: ; 2 Lewis T, 1925; ; 3 Allessie, 1971; 4 Skanes Circulation 1998; ; 5 Vaquero/Jalife Heart Rhythm 2008; ; 6 Comtois, Nattel. Chaos, 2011

8 Does Mechanism Explain Therapeutic Success? Roof rotor was stable during PVI (WACA), until eliminated during roof ablation. Did Ablation Pass through Rotor? Blinded to acute/chronic outcomes Inter-observer κ = 0.89 Narayan, Krummen, Clopton, Shivkumar, Miller, Direct or Coincidental Elimination of Sources Explains Success of AF Ablation. JACC 2013; jacc [Epub]

9 New Mechanistic Direction in AF Therapy Ablation of All Rotors Ablation of 1 Rotor/Source Did Ablation Pass through Rotor? Blinded to acute/chronic outcomes Inter-observer κ = 0.89 All cases 1 st Atrial Fibrillation (even Paroxysmal AF) is a substrate Based disease All All Cases Rotors Missed Ablation Missed All Sources 1 st Ablation of Some Rotors Narayan, Krummen, Clopton, Shivkumar, Miller, Direct or Coincidental Elimination of Sources Explains Success of AF Ablation. JACC 2013; jacc [Epub]

10 Clinical Translation : FIRM Only Ablation Median 223 days followup FIRM only. PRECISE. 82.6% Prospective Targeted Ablation of Stable Rotors/Focal (64.5% ) (FIRM+PVI CONFIRM TRIAL) Sources Will Eliminate Paroxysmal AF Long Term Without PVI PVI, STOP-AF Packer, JACC 2013: PVI, RAAFT-2. LBCT HRS 2012 PRECISE-PAF: Precise Rotor Elimination without Concomitant pulmonary vein MANTRA-AF, Nielsen NEJM 2012: Isolation for the Successful Elimination of Paroxysmal AF (clinicaltrials.gov: NCT , 2010)

11 Cellular/Tissue Ablation? Narayan/Franz, Circ 2002, 2011 Kim et al., JACC 2002 AF: Connexin 40 GJA5 Mutation; Gollob 2005 Cutler/Rosenbaum Rx: SERCA2a Abolishes APD Alt (animal ventricles) Suppress Reentry Regionally? Marrouche et al. Spragg/Calkins, HR 2012 Connexin40 gene speeds conduction prevents AF; Igarashi/Donahue 2012 Narayan/Franz et al., Circulation 2002; Circulation 2011; Cutler/Rosenbaum, Circ EP 2009; 2(6): Roberts & Gollob (2010). JACC 55(8): ; Igarashi, Donahue et al., Circulation 2012; 125(2): ; Darbar & Roden (2013). Nat Rev Cardiovasc Med; Epub

12 Future: Making Ablation More Efficient, Safer Image Integration Reddy. Fluoroless ablation Buch, Shivkumar Pericardial Insulation Courtesy, M.Orlov Kuck et al, Monitor Catheter Contact Buch. Heart Rhythm 2007; 4(1): 95-98; Reddy. Heart Rhythm 2010; 7(11): ; Kuck et al., TOCCATA Study. Heart Rhythm 2012; 9(1):

13 Ventricular Arrhythmias Target the Mechanism Better Ablation OR Ablate Yan, Circulation 2006; 114: PREDICTION PREVENTION Quantify candidate VT Isthmuses Computational Maps

14 Novel VT Isthmus Mapping Ciaccio/Peters. Computational Delineation of VT Isthmus in Sinus Rhythm. Heart Rhythm 2008; 5(7): Ashikaga, Porcine VT; Circ Res 2007;101(9): Wu, Circulation Diffusion Tensor MRI. Fiber Angles Nazarian, NICM Scar; Circulation 2005;112:2821

15 Cellular/Tissue Ablation? Connexin 43 improves conduction, reduces VT Inducibility. Greener/Donahue 2012 Modulation of APD to prevent reentry Sasano/Donahu e; Nat Med 2006 Sasano, Donahue et al. (2006). "Molecular ablation of VT." Nat Med 12(11): Cutler, Rosenbaum (2009). "Targeted SERCA2a alternans." Circ A/E 2(6): Greener, Donahue (2012). "Connexin43 reduces VT" JACC 60(12):

16 Novel Approaches to VT Substrate Modification Collagenase Therapy Courtesy of Yagishita/Shivkumar Ablation Homogenization Di Biase/Natale, JACC 2012

17 Conclusion Back to the future is the mantra to extend the classic approach to refine mechanistic understanding, hand-inhand with novel therapeutic innovations. Technologies we are more likely to see in the future Computational mapping Tissue Characterization by DE-MRI, DT-MRI, other Characterization of the Neural substrate Improved and safer energy delivery methods Convergence of new mechanistic ideas and technologies continues the spirit of our pioneers in the field.

18 The Future: Addressing Inequalities in Delivery