9/11/2019 Mixed Results from Clinical Electrode Mapping Studies on - - PDF document

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"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

• 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

Significance of AF studies

Mixed Results from Clinical Electrode Mapping Studies on AF Mechanisms Finding Order within Chaos to Treat AF

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Fedorov Lab Projects:

The Beating Human Heart Ex Vivo

Translational AF Studies at The OSU to improve AF Driver detection and ablation

Hansen et al., European Heart J 2015; Zhao et al., Circulation A&E 2015; Li et al Circulation 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 TM 2017, Zhao et al., JAHA 2017; Hansen et al., JACC EP 2018; Hansen, Li et al Circulation A&E 2018

T m

Drs

he OSU Human Heart Progra

2012‐2019

175 hearts

(Drs. Paul Janssen and Peter Mohler) . Nahush Mokadam and Bryan Whitson: cardiacsu

Unused Donor Hearts Failing Hearts

rgery

• 1. Ex‐vivo Human Heart:

Optical, Multi‐Electrode and 3D DE‐MRI Structural Mapping

2.In‐Vivo Clinical studies:

Multi‐Electrode Mapping and 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

Similarities of Clinical and Ex vivo Human Atrial Activation and Repolarization

Zhao et al., Circulation A&E, 2015 and Li et al., Circulation 2016

Panoramic Optical mapping with Near‐Infrared voltage sensitive dye di‐4‐ANBDQBS, Four High‐Resolution UltimaL CMOS Cameras (100x100 pixels, 1 ms)

In ex vivo experiments, AF driver DF is ~5‐13 Hz

Hansen et al., European Heart J 2015; Zhao et al Circ A&E 2015 Li et al., Circulation 2016, Hansen et al JACC EP 2018

Mapping of Human AF ex vivo : Dominant Frequency (DF) and Activation Mapping

63 y.o. Female, HTN/CAD/DM Reentrant Driver in RA

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Mapping of Human AF ex vivo: Only One-Side Mapping may not be Enough!

Li et al., Circulation2016

Panoramic Camera 9x9cm2 900µm resolution 30,000 OAP Recordings!!! Dual-Sided Cameras 300µm resolution

Contrast-Enhanced (CE)

3D MRI (80mm3)

Hansen et al., European Heart J, 2015 AF Driver Visualization Pattern Endo Epicardium Reentry 17 (85%) 8 (40%) Breakthrough 3 (15%) 12 (60%) Total Drivers in 13 Human Atria 20 20

Mapping of Human AF ex vivo : Simultaneous Sub-Endo and Sub-Epi NIOM

Localized Reentrant or Breakthrough/Focal activation patterns in Human AF, can both represent Intramural Microanatomic Reentries

Hansen et al., European Heart J 2015; Li et al., Circulation 2016, Zhao et al JAHA 2017

From the Research Lab to the Bedside:

Validating Clinical Multi-electrode Mapping by 3D Functional and Structural Imaging in ex vivo Human Hearts

Hansen et al., JACC EP 2018

30,000OAP Recordings Dual‐Sided Cameras 300µm resolution

Simultaneous Endo‐Epicardial Optical Mapping Custom FIRM catheters and RhythmView 6.1 provided by Abbott Electrophysiology

Customized Flat 64‐Electrode Catheters by Abbott Engineers (Brian Pederson)

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3D Human Atrial Fibrotic Structure Provides a Challenge for Clinical Surface Electrode Mapping of AF sources

Hansen et al., JACC EP 2018

Ex-vivo Human Heart: DF Domain Frequency and AF Driver

Surface MEM Visualizes Focal Patterns of Intramural AF Reentrant Drivers

Hansen et al., JACC EP 2018

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

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True Driver and False Positive RAP Detected by Clinical MEM

Hansen et al., JACC EP 2018

Can electrogram features surpass classical conduction mapping in AF driver detection?

Hansen, Fedorov et al., under preparation 2019 Zaman et al., Circulation A&E 2018

Ex-Vivo Human Heart: Multi-Electrode Mapping can Misinterpret Reentry as Multi-Breakthroughs

All MEM NIOM MEM Activation MEM Wave Reentry 71% 54% 38% Breakthrough 29% 25% 0% Multi-Wavelets 0% 21% 62%

Hansen et al. HRS 2019 May 9th No Targets Hansen et al., J Am Coll Cardiol EP 2018

3D Fibrosis Architecture of Human Reentrant AF Drivers (n=40+)

Contrast-Enhanced MRI ex vivo Resolution ~80-180μm3 (9.4T)

Hansen et al., EHJ 2015; Zhao et al., JAHA 2017; Hansen et al., JACC EP 2018

RA LA

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3D Structural “Fingerprints” of the AF Driver:

Intramural Fibrosis, Endo-Epi Myofiber Twist, Thickness Variation, CE-MRI ex vivo Resolution 80-180μm3 (9.4T)

Hansen, Zhao, Hummel, Fedorov et al., EHJ 2015 Hansen, Zhao and Fedorov, JACC EP 2017 and 2018 Zhao, Hansen, Hummel, Fedorov et al., JAHA 2017

3D Distribution of Fibrosis can distinguish True from False Positive Drivers

Hansen et al JACC EP, 2018 Hansen et al., European Heart J 2015 Gal and Marrouche, JACC EP 2017 Zhao, Hansen, Fedorov et al., JAHA 2017 80mm

3

Clinical in-vivo DE-MRI limitations to image Atrial Wall Variation and Intramural Fibrosis In vivo Resolution 1250μm3 Ex vivo Resolution 80-180μm3

Is There Hope for Identifying AF Driver Substrates In-Vivo?

Cochet, Jais et al., JACC EP 2018

Relationship between DE-MRI Fibrosis and ECGI Reentrant Activity in Human Persistent AF

Box Isolation

• f FibroticArea

BiFA

Kottkamp et al., JCE 2016

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Translational Framework: Integrating Ex-Vivo, In-Silico, and In-Vivo Datasets for Successful AF Driver Ablation

Hansen, Helfrich, Zhao, Simonetti, Hummel, Fedorov et al., under review 2019

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

Li et al., Circulation 2016

Gi Gbg GIRK1 GIRK4

IK,Ado Tertiapin A1R Adenosine

Ex-Vivo Human Heart: Adenosine-induced atrial repolarization modulation and AF Ex-Vivo and In-Silico: Adenosine Challenge May increase Visualization of Reentrant Drivers to Improve Targeted Ablation

Hansen, Helfrich, Zhao, Simonetti, Hummel, Fedorov et al., under review 2019

Translational In-Silico: Crucial Role of Driver Fibrosis for AF induction

Hansen, Helfrich, Zhao, Simonetti, Hummel, Fedorov et al., under review 2019

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Clinical: Integrating MEM and 3D DE-MRI Fibrosis Analysis to Discriminate Reentrant Drivers of Persistent AF

Hansen, Helfrich, Zhao, Simonetti, Hummel, Fedorov et al., under review 2019

Translational: Mutual Validation of In-vivo and Ex-vivo MEM, NIOM, and 3D DE-MRI to Improve Patient-specific Targeted AF Treatment

HD grid and 64- electrodes Basket Ex-Vivo NIOM Validation of Reentrant AF Drivers Locations In-Vivo MEM of Reentrant AF Drivers in the Persistent AF Canine (>4 month) with fibrotic remodeling 3D DE-MRI

Fedorov lab 2019 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

Translational: First In-Vivo Near-Infrared Optical Mapping (NIOM) and MEM of Canine AF

Hansen, Li, Fedorov et al. Circulation A&E 2018;11(12):e006870.

Translational: In-Vivo Atrial Activation during Atrial Pacing and Sinus Rhythm as Seen by NIOM and MEA

Hansen, Li, Fedorov et al. Circulation A&E 2018;11(12):e006870.

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Hansen, Li, Fedorov et al. Circulation A&E 2018;11(12):e006870.

Translational: First In-Vivo NIOM and MEM of Canine AF

RAO Fluoroscopywith Basket Catheter

Finding Order within Chaos to Treat AF The Honey Badgers Team

John Hummel and Raul Weiss: clinical EP Orlando Simonetti: 3D CE MRI

Nahush Mokadam and Bryan Whitson: cardiac surgery Peter Mohler and Paul Janssen: explanted human hearts Richard Schuessler, Washington University Eugene Kholmovski, University of Utah

Dmitry Dylov, Skoltech, Moscow Jichao Zhao,

University of Auckland, New Zealand

Source of Funding:

NIH R01 HL115580, HL135109, AHA Grant in Aid Davis Heart and Lung Research Institute TriFit Ross hospital fund, Abbott laboratory Frick Center for Arrhythmia and Heart Failure Lhota Family Fund for Cardiovascular Research Fedorov Lab Team: Brian Hansen and Ning Li

Katelynn Helfrich, Anu Kalyanasundaram, Esthela Artiga, Suhaib Abudulwahed, Alex Iancau and Alexander Zolotorev

Vadim.Fedorov@osumc.edu

Questions?

vadim.fedorov@osumc.edu

5196 (office) and 5040 (lab) Graves Hall