title: Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts.
abstract: OBJECTIVE
  The complex architecture of the human atria may create physical substrates for sustained re-entry to drive atrial fibrillation (AF). The existence of sustained, anatomically defined AF drivers in humans has been challenged partly due to the lack of simultaneous endocardial-epicardial (Endo-Epi) mapping coupled with high-resolution 3D structural imaging.
  
  
  RESULTS
  Coronary-perfused human right atria from explanted diseased hearts (n = 8, 43-72 years old) were optically mapped simultaneously by three high-resolution CMOS cameras (two aligned Endo-Epi views (330 µm2 resolution) and one panoramic view). 3D gadolinium-enhanced magnetic resonance imaging (GE-MRI, 80 µm3 resolution) revealed the atrial wall structure varied in thickness (1.0 ± 0.7-6.8 ± 2.4 mm), transmural fiber angle differences, and interstitial fibrosis causing transmural activation delay from 23 ± 11 to 43 ± 22 ms at increased pacing rates. Sustained AF (>90 min) was induced by burst pacing during pinacidil (30-100 µM) perfusion. Dual-sided sub-Endo-sub-Epi optical mapping revealed that AF was driven by spatially and temporally stable intramural re-entry with 107 ± 50 ms cycle length and transmural activation delay of 67 ± 31 ms. Intramural re-entrant drivers were captured primarily by sub-Endo mapping, while sub-Epi mapping visualized re-entry or 'breakthrough' patterns. Re-entrant drivers were anchored on 3D micro-anatomic tracks (15.4 ± 2.2 × 6.0 ± 2.3 mm2, 2.9 ± 0.9 mm depth) formed by atrial musculature characterized by increased transmural fiber angle differences and interstitial fibrosis. Targeted radiofrequency ablation of the tracks verified these re-entries as drivers of AF.
  
  
  CONCLUSIONS
  Integrated 3D structural-functional mapping of diseased human right atria ex vivo revealed that the complex atrial microstructure caused significant differences between Endo vs. Epi activation during pacing and sustained AF driven by intramural re-entry anchored to fibrosis-insulated atrial bundles.
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, 300 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hansen
authors.affiliation: Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand.
authors.forename: Jichao
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, 300 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Csepe
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, 300 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA.
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Moore
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, 300 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, 300 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Jayne
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, 300 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kalyanasundaram
authors.affiliation: Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand.
authors.forename: Praise
authors.initials: P
authors.lastname: Lim
authors.affiliation: Small Animal Imaging Core, The Ohio State University Wexner Medical Center, Columbus, OH, USA Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Bratasz
authors.affiliation: Small Animal Imaging Core, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Kimerly A
authors.initials: KA
authors.lastname: Powell
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Orlando P
authors.initials: OP
authors.lastname: Simonetti
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Robert S D
authors.initials: RS
authors.lastname: Higgins
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kilic
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, 300 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, 300 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Weiss
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Hummel
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, 300 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA vadim.fedorov@osumc.edu vadimfed@gmail.com.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Fedorov
mesh_terms: D000328:Adult; D000368:Aged; D001281:Atrial Fibrillation / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D057791:Cardiac Imaging Techniques; D003287:Contrast Media; D056149:Epicardial Mapping / Q000379:methods; D005682:Gadolinium; D006325:Heart Atria / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D018810:Magnetic Resonance Angiography / Q000379:methods; D008875:Middle Aged
chemical_list: D003287:Contrast Media; D005682:Gadolinium
keywords: Atrial fibrillation; Catheter radiofrequency ablation; Fibrosis; Gadolinium-enhanced MRI; Intramural re-entry; Optical mapping; Rotor