title: Increased Susceptibility to Atrial Fibrillation Secondary to Atrial Fibrosis in Transgenic Goats Expressing Transforming Growth Factor-β1.
abstract: Large animal models of progressive atrial fibrosis would provide an attractive platform to study relationship between structural and electrical remodeling in atrial fibrillation (AF). Here we established a new transgenic goat model of AF with cardiac specific overexpression of TGF-β1 and investigated the changes in the cardiac structure and function leading to AF.
  
  
  
  Transgenic goats with cardiac specific overexpression of constitutively active TGF-β1 were generated by somatic cell nuclear transfer. We examined myocardial tissue, ECGs, echocardiographic data, and AF susceptibility in transgenic and wild-type control goats. Transgenic goats exhibited significant increase in fibrosis and myocyte diameters in the atria compared to controls, but not in the ventricles. P-wave duration was significantly greater in transgenic animals starting at 12 months of age, but no significant chamber enlargement was detected, suggesting conduction slowing in the atria. Furthermore, this transgenic goat model exhibited a significant increase in AF vulnerability. Six of 8 transgenic goats (75%) were susceptible to AF induction and exhibited sustained AF (>2 minutes), whereas none of 6 controls displayed sustained AF (P < 0.01). Length of induced AF episodes was also significantly greater in the transgenic group compared to controls (687 ± 212.02 seconds vs. 2.50 ± 0.88 seconds, P < 0.0001), but no persistent or permanent AF was observed.
  
  
  
  A novel transgenic goat model with a substrate for AF was generated. In this model, cardiac overexpression of TGF-β1 led to an increase in fibrosis and myocyte size in the atria, and to progressive P-wave prolongation. We suggest that these factors underlie increased AF susceptibility.
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Polejaeva
authors.affiliation: CARMA Center, Division of Cardiology, University of Utah, Salt Lake City, UT.|Department of Bioengineering, University of Utah, Salt Lake City, UT.
authors.forename: Ravi
authors.initials: R
authors.lastname: Ranjan
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Davies
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Misha
authors.initials: M
authors.lastname: Regouski
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Justin
authors.initials: J
authors.lastname: Hall
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Olsen
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Qinggang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Heloisa M
authors.initials: HM
authors.lastname: Rutigliano
authors.affiliation: Center for Engineering Innovation, University of Utah, Salt Lake City, UT.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Dosdall
authors.affiliation: CARMA Center, Division of Cardiology, University of Utah, Salt Lake City, UT.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Angel
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT.|Department of Bioengineering, University of Utah, Salt Lake City, UT.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Sachse
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seidel
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Thomas
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Rusty
authors.initials: R
authors.lastname: Stott
authors.affiliation: USDA ARS Poisonous Plant Research Laboratory, Logan, UT.
authors.forename: Kip E
authors.initials: KE
authors.lastname: Panter
authors.affiliation: College of Veterinary Medicine, Washington State University, Pullman, WA.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Lee
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Arnaud J
authors.initials: AJ
authors.lastname: Van Wettere
authors.affiliation: Department of Mathematics and Statistics, Utah State University, Logan, UT.
authors.forename: John R
authors.initials: JR
authors.lastname: Stevens
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Zhongde
authors.initials: Z
authors.lastname: Wang
authors.affiliation: CARMA Center, Division of Cardiology, University of Utah, Salt Lake City, UT.|Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT.
authors.forename: Rob S
authors.initials: RS
authors.lastname: MacLeod
authors.affiliation: CARMA Center, Division of Cardiology, University of Utah, Salt Lake City, UT.
authors.forename: Nassir F
authors.initials: NF
authors.lastname: Marrouche
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: White
mesh_terms: D000200:Action Potentials; D000818:Animals; D030801:Animals, Genetically Modified; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D064752:Atrial Remodeling; D001706:Biopsy; D004452:Echocardiography; D004562:Electrocardiography; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006041:Goats / Q000235:genetics*; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D018613:Microscopy, Confocal; D010641:Phenotype; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1
keywords: TGF-β1 transgenic goat model; atrial fibrillation; fibrosis; genetics