title: Constitutive Expression of a Dominant-Negative TGF-β Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate.
abstract: Fibrosis is an important structural contributor to formation of atrial fibrillation (AF) substrate in heart failure. Transforming growth factor-β (TGF-β) signaling is thought to be intricately involved in creation of atrial fibrosis.
  
  
  
  We hypothesized that gene-based expression of dominant-negative type II TGF-β receptor (TGF-β-RII-DN) in the posterior left atrium in a canine heart failure model will sufficiently attenuate fibrosis-induced changes in atrial conduction and restitution to decrease AF. Because AF electrograms are thought to reflect AF substrate, we further hypothesized that TGF-β-RII-DN would lead to increased fractionation and decreased organization of AF electrograms.
  
  
  
  Twenty-one dogs underwent injection+electroporation in the posterior left atrium of plasmid expressing a dominant-negative TGF-β type II receptor (pUBc-TGFβ-DN-RII; n=9) or control vector (pUBc-LacZ; n=12), followed by 3 to 4 weeks of right ventricular tachypacing (240 bpm). Compared with controls, dogs treated with pUBC-TGFβ-DN-RII demonstrated an attenuated increase in conduction inhomogeneity, flattening of restitution slope and decreased duration of induced AF, with AF electrograms being more fractionated and less organized in pUBc-TGFβ-DN-RII versus pUBc-LacZ dogs. Tissue analysis revealed a significant decrease in replacement/interstitial fibrosis, p-SMAD2/3 and p-ERK1/2.
  
  
  
  Targeted gene-based reduction of TGF-β signaling in the posterior left atrium-with resulting decrease in replacement fibrosis-led to beneficial remodeling of both conduction and restitution characteristics of the posterior left atrium, translating into a decrease in AF and increased complexity of AF electrograms. In addition to providing mechanistic insights, this data may have important diagnostic and therapeutic implications for AF.
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Aaron
authors.initials: A
authors.lastname: Kunamalla
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Jason
authors.initials: J
authors.lastname: Ng
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Vamsi
authors.initials: V
authors.lastname: Parini
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Shin
authors.initials: S
authors.lastname: Yoo
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Kate A
authors.initials: KA
authors.lastname: McGee
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Todd T
authors.initials: TT
authors.lastname: Tomson
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: David
authors.initials: D
authors.lastname: Gordon
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Thorp
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Jon
authors.initials: J
authors.lastname: Lomasney
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Shah
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Browne
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Knight
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Rod
authors.initials: R
authors.lastname: Passman
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Goldberger
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL.
authors.forename: Gary
authors.initials: G
authors.lastname: Aistrup
authors.affiliation: From the Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL. r-arora@northwestern.edu.
authors.forename: Rishi
authors.initials: R
authors.lastname: Arora
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001281:Atrial Fibrillation / Q000628:therapy*; D016275:Atrial Function; D004285:Dogs; D005355:Fibrosis; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: atrial fibrillation; electroporation; fibrosis; gene therapy; heart failure