9/11/2019 Mixed Results from Clinical Electrode Mapping Studies on AF Mechanisms "Mechanism of AF Using Integrated Optical and Multi-Electrode Mapping of Human Hearts” Vadim V. Fedorov, PhD Professor of Physiology and Cell Biology San Francisco, September 14, 2019 Significance of AF studies Finding Order within Chaos to Treat AF • Most prevalent sustained arrhythmia in the US and Russia • AF leads to diminished quality of life, heart failure, and morbidity • Leading cause of Stroke • Treatment of AF is an increasing economic burden • Mechanism of AF in the Human Heart is still Unclear 1
9/11/2019 Fedorov Lab Projects: Similarities of Clinical and Ex vivo Human Atrial Activation and Repolarization The Beating Human Heart Ex Vivo Panoramic Optical mapping with Near‐Infrared voltage sensitive dye di‐4‐ANBDQBS, Four High‐Resolution UltimaL CMOS Cameras (100x100 pixels, 1 ms) Zhao et al., Circulation A&E , 2015 and Li et al., Circulation 2016 Translational AF Studies at The OSU Mapping of Human AF ex vivo : to improve AF Driver detection and ablation Dominant Frequency (DF) and Activation Mapping T he OSU Human Heart Progra m Reentrant Driver in RA 63 y.o. Female, HTN/CAD/DM 2012‐2019 1. Ex‐vivo Human Heart: 175 hearts Optical, Multi‐Electrode and (Drs. Paul Janssen and Peter Mohler) 3D DE‐MRI Structural Mapping Drs . Nahush Mokadam and Bryan Whitson: cardiacsu rgery Unused Donor Hearts 2.In‐Vivo Clinical studies: Multi‐Electrode Mapping and Failing Hearts 2D DE‐MRI Of Persistent AF Patients John Hummel and Orlando Simonetti et al 3. In‐vivo Translational studies: Canine Model of Persistent AF with In‐vivo Optical Mapping Hansen et al., European Heart J 2015; Zhao et al., Circulation A&E 2015; Li et al Circulation In ex vivo experiments, AF driver DF is ~5‐13 Hz A&E 2015; Li et al., Circulation 2016, Hansen et al., Circulation A&E 2016; Csepe et al., European Heart J Cardiovac Imaging 2017; Hansen et al., JACC EP 2017. Li et al., Science Hansen et al ., European Heart J 2015; Zhao et al Circ A&E 2015 TM 2017, Zhao et al., JAHA 2017; Hansen et al., JACC EP 2018; Hansen, Li et al Circulation A&E 2018 Li et al., Circulation 2016, Hansen et al JACC EP 2018 2
9/11/2019 Localized Reentrant or Breakthrough/Focal activation Mapping of Human AF ex vivo : Only One-Side Mapping may not be Enough! patterns in Human AF, can both represent Intramural Microanatomic Reentries Li et al., Circulation 2016 Hansen et al ., European Heart J 2015; Li et al., Circulation 2016, Zhao et al JAHA 2017 From the Research Lab to the Bedside: Mapping of Human AF ex vivo : Simultaneous Sub-Endo and Sub-Epi NIOM Validating Clinical Multi-electrode Mapping by 3D Functional and Structural Imaging in ex vivo Human Hearts 30,000 OAP Recordings!!! Dual-Sided Cameras 300µm resolution Panoramic Camera 9x9cm 2 900µm resolution Simultaneous Customized Flat Endo‐Epicardial 64‐Electrode Contrast-Enhanced (CE) Optical Mapping 3D MRI (80mm 3 ) AF Driver Visualization Catheters by 30,000OAP Pattern Endo Epicardium Recordings Custom FIRM catheters and RhythmView 6.1 Abbott provided by Abbott Electrophysiology Dual‐Sided Engineers Cameras Reentry 17 (85%) 8 (40%) 300µm (Brian Pederson) resolution Breakthrough 3 (15%) 12 (60%) Total Drivers in 13 20 20 Human Atria Hansen et al., European Heart J , 2015 Hansen et al., JACC EP 2018 3
9/11/2019 3D Human Atrial Fibrotic Structure Provides a Challenge Surface MEM Visualizes Focal Patterns of for Clinical Surface Electrode Mapping of AF sources Intramural AF Reentrant Drivers Hansen et al., JACC EP 2018 Ex-vivo Human Heart: DF Domain Frequency and AF Driver Validation of Clinical MEM-defined Human AF Drivers by NIOM FIRM RAP Data Analyzed Blinded to Optical Data by Abbott Engineers Hansen et al., JACC EP 2018 Hansen et al., JACC EP 2018 4
9/11/2019 True Driver and False Positive RAP Detected by Ex-Vivo Human Heart: Multi-Electrode Mapping can Clinical MEM Misinterpret Reentry as Multi-Breakthroughs Hansen et al., J Am Coll Cardiol EP 2018 No Targets All MEM NIOM MEM Activation MEM Wave Reentry 71% 54% 38% Hansen et al., JACC EP 2018 Hansen et al. Breakthrough 29% 25% 0% HRS 2019 Multi-Wavelets 0% 21% 62% May 9 th Can electrogram features surpass classical conduction 3D Fibrosis Architecture of mapping in AF driver detection? Human Reentrant AF Drivers (n=40+) Contrast-Enhanced MRI ex vivo Resolution ~80-180μm 3 (9.4T) Zaman et al., Circulation A&E 2018 Hansen, Fedorov et al., under preparation 2019 RA LA Hansen et al., EHJ 2015 ; Zhao et al., JAHA 2017; Hansen et al., JACC EP 2018 5
9/11/2019 3D Structural “Fingerprints” of the AF Driver: Is There Hope for Identifying AF Driver Substrates In-Vivo ? Clinical in-vivo DE-MRI limitations to image Intramural Fibrosis, Endo-Epi Myofiber Twist, Thickness Variation, Atrial Wall Variation and Intramural Fibrosis CE-MRI ex vivo Resolution 80-180μm 3 (9.4T) In vivo Resolution 1250μm 3 Ex vivo Resolution 80-180μm 3 Zhao, Hansen, Fedorov et al., JAHA 2017 80mm 3 Hansen, Zhao, Hummel, Fedorov et al., EHJ 2015 Hansen et al., European Heart J 2015 Gal and Marrouche, JACC EP 2017 Hansen, Zhao and Fedorov , JACC EP 2017 and 2018 Zhao, Hansen, Hummel, Fedorov et al., JAHA 2017 3D Distribution of Fibrosis can distinguish Relationship between DE-MRI Fibrosis and ECGI True from False Positive Drivers Reentrant Activity in Human Persistent AF Box Isolation of FibroticArea BiFA Kottkamp et al., JCE 2016 Hansen et al JACC EP , 2018 Cochet, Jais et al., JACC EP 2018 6
9/11/2019 Translational Framework: Integrating Ex-Vivo , In-Silico , and In-Vivo Ex-Vivo and In-Silico : Adenosine Challenge May increase Datasets for Successful AF Driver Ablation Visualization of Reentrant Drivers to Improve Targeted Ablation Hansen, Helfrich, Zhao, Simonetti, Hummel, Fedorov et al., under review 2019 Hansen, Helfrich, Zhao, Simonetti, Hummel, Fedorov et al., under review 2019 Translational In-Silico : Ex-Vivo Human Heart: Adenosine-induced atrial repolarization modulation and AF Crucial Role of Driver Fibrosis for AF induction Adenosine A1R G i GIRK1 Tertiapin G bg GIRK4 I K,Ado Clinical DF and MAP studies support RA-to-LA APD gradient after Adenosine Bolus: Botteron and Smith, JCE 1994 Atienza et al., Circulation 2006 Krummen et al., Circulation A&E 2012 Hansen, Helfrich, Zhao, Simonetti, Hummel, Fedorov et al., under review 2019 Li et al., Circulation 2016 7
9/11/2019 Clinical: Integrating MEM and 3D DE-MRI Fibrosis Analysis Translational: First In-Vivo Near-Infrared Optical Mapping to Discriminate Reentrant Drivers of Persistent AF (NIOM) and MEM of Canine AF Staining: 10mL of warm saline-diluted near-infrared di-4-ANB6QBS, 1.5mg, was delivered in Right or Left coronary artery (RCA) during 20-30s a Multi-electrode catheters were provided by Abbott EP Hansen, Helfrich, Zhao, Simonetti, Hummel, Fedorov et al., under review 2019 Hansen, Li, Fedorov et al. Circulation A&E 2018;11(12):e006870 . Translational: In-Vivo Atrial Activation during Atrial Pacing and Sinus Rhythm Translational: Mutual Validation of In-vivo and Ex-vivo MEM, NIOM, and as Seen by NIOM and MEA 3D DE-MRI to Improve Patient-specific Targeted AF Treatment In-Vivo MEM of Reentrant AF Drivers in the Persistent AF Canine (>4 month) with fibrotic remodeling HD grid and 64- 3D DE-MRI electrodes Basket Ex-Vivo NIOM Validation of Reentrant AF Drivers Locations Hansen, Li, Fedorov et al. Circulation A&E 2018;11(12):e006870 . Fedorov lab 2019 8
9/11/2019 The Honey Badgers Team Translational: First In-Vivo NIOM and MEM of Canine AF Vadim.Fedorov@osumc.edu RAO Fluoroscopywith Jichao Zhao, Fedorov Lab Team: Brian Hansen and Ning Li University of Auckland, Basket Catheter Katelynn Helfrich, Anu Kalyanasundaram, Esthela Artiga, New Zealand Suhaib Abudulwahed, Alex Iancau and Alexander Zolotorev John Hummel and Raul Weiss : clinical EP Source of Funding: Orlando Simonetti: 3D CE MRI NIH R01 HL115580, HL135109, AHA Grant in Aid Nahush Mokadam and Bryan Whitson: cardiac surgery Davis Heart and Lung Research Institute TriFit Peter Mohler and Paul Janssen: explanted human hearts Ross hospital fund, Abbott laboratory Frick Center for Arrhythmia and Heart Failure Richard Schuessler, Washington University Lhota Family Fund for Cardiovascular Research Eugene Kholmovski, University of Utah Dmitry Dylov , Skoltech, Moscow Hansen, Li, Fedorov et al. Circulation A&E 2018;11(12):e006870 . Finding Order within Chaos to Treat AF Questions? vadim.fedorov@osumc.edu 5196 (office) and 5040 (lab) Graves Hall 9
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