title: Electrophysiological, Electroanatomical, and Structural Remodeling of the Atria as Consequences of Sustained Obesity.
abstract: BACKGROUND
  Obesity and atrial fibrillation (AF) are public health issues with significant consequences.
  
  
  OBJECTIVE
  This study sought to delineate the development of global electrophysiological and structural substrate for AF in sustained obesity.
  
  
  METHODS
  Ten sheep fed ad libitum calorie-dense diet to induce obesity over 36 weeks were maintained in this state for another 36 weeks; 10 lean sheep with carefully controlled weight served as controls. All sheep underwent electrophysiological and electroanatomic mapping; hemodynamic and imaging assessment (echocardiography and dual-energy x-ray absorptiometry); and histology and molecular evaluation. Evaluation included atrial voltage, conduction velocity (CV), and refractoriness (7 sites, 2 cycle lengths), vulnerability for AF, fatty infiltration, atrial fibrosis, and atrial transforming growth factor (TGF)-β1 expression.
  
  
  RESULTS
  Compared with age-matched controls, chronically obese sheep demonstrated greater total body fat (p < 0.001); LA volume (p < 0.001); LA pressure (p < 0.001), and PA pressures (p < 0.001); reduced atrial CV (LA p < 0.001) with increased conduction heterogeneity (p < 0.001); increased fractionated electrograms (p < 0.001); decreased posterior LA voltage (p < 0.001) and increased voltage heterogeneity (p < 0.001); no change in the effective refractory period (ERP) (p > 0.8) or ERP heterogeneity (p > 0.3). Obesity was associated with more episodes (p = 0.02), prolongation (p = 0.01), and greater cumulative duration (p = 0.02) of AF. Epicardial fat infiltrated the posterior LA in the obese group (p < 0.001), consistent with reduced endocardial voltage in this region. Atrial fibrosis (p = 0.03) and TGF-β1 protein (p = 0.002) were increased in the obese group.
  
  
  CONCLUSIONS
  Sustained obesity results in global biatrial endocardial remodeling characterized by LA enlargement, conduction abnormalities, fractionated electrograms, increased profibrotic TGF-β1 expression, interstitial atrial fibrosis, and increased propensity for AF. Obesity was associated with reduced posterior LA endocardial voltage and infiltration of contiguous posterior LA muscle by epicardial fat, representing a unique substrate for AF.
authors.affiliation: Centre for Heart Rhythm Disorders (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Mahajan
authors.affiliation: Centre for Heart Rhythm Disorders (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Lau
authors.affiliation: Centre for Heart Rhythm Disorders (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Brooks
authors.affiliation: Centre for Heart Rhythm Disorders (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Shipp
authors.affiliation: School of Medical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Jim
authors.initials: J
authors.lastname: Manavis
authors.affiliation: Royal Adelaide Hospital and Department of Ophthalmology, University of Adelaide, Adelaide, Australia.
authors.forename: John P M
authors.initials: JP
authors.lastname: Wood
authors.affiliation: SA Pathology, Adelaide, Australia.
authors.forename: John W
authors.initials: JW
authors.lastname: Finnie
authors.affiliation: Department of Pharmacology, Monash University, Melbourne, Australia.
authors.forename: Chrishan S
authors.initials: CS
authors.lastname: Samuel
authors.affiliation: Department of Pharmacology, Monash University, Melbourne, Australia.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Royce
authors.affiliation: Centre for Heart Rhythm Disorders (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: Darragh J
authors.initials: DJ
authors.lastname: Twomey
authors.affiliation: Centre for Heart Rhythm Disorders (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: Shivshanker
authors.initials: S
authors.lastname: Thanigaimani
authors.affiliation: Department of Cardiology, Royal Melbourne Hospital and Department of Medicine, University of Melbourne, Melbourne, Australia.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kalman
authors.affiliation: Centre for Heart Rhythm Disorders (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia. Electronic address: prash.sanders@adelaide.edu.au.
authors.forename: Prashanthan
authors.initials: P
authors.lastname: Sanders
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000473:pathology; D064752:Atrial Remodeling; D022062:Electrophysiologic Techniques, Cardiac; D005355:Fibrosis; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006329:Heart Conduction System / Q000503:physiopathology*; D006439:Hemodynamics; D009765:Obesity / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D012756:Sheep; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D053773:Transforming Growth Factor beta1
keywords: TGF-β1; atrial fibrillation; epicardial fat; fibrosis; obesity