Constitutive Expression of a Dominant-Negative TGF-β Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate

Circ Res. 2016 Jun 24;119(1):69-82. doi: 10.1161/CIRCRESAHA.115.307878. Epub 2016 May 23.

Abstract

Rationale: 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.

Objective: 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.

Methods and results: 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.

Conclusions: 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.

Keywords: atrial fibrillation; electroporation; fibrosis; gene therapy; heart failure.

MeSH terms

  • 3T3 Cells
  • Animals
  • Atrial Fibrillation / therapy*
  • Atrial Function
  • Dogs
  • Fibrosis
  • Genetic Therapy*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Heart Atria / metabolism*
  • Heart Atria / pathology
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Smad Proteins / metabolism

Substances

  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Receptor, Transforming Growth Factor-beta Type II