Constitutive expression of a dominant-negative TGF-β type II receptor in the posterior left atrium leads to beneficial remodeling of atrial fibrillation substrate

Aaron Kunamalla, Jason Ng, Vamsi Parini, Shin Yoo, Kate A. Mcgee, Todd T. Tomson, David Gordon, Edward B. Thorp, Jon Lomasney, Qiang Zhang, Sanjiv Shah, Suzanne Browne, Bradley P. Knight, Rod Passman, Jeffrey Goldberger, Gary Aistrup, Rishi Arora

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)69-82
Number of pages14
JournalCirculation Research
Volume119
Issue number1
DOIs
StatePublished - Jun 24 2016
Externally publishedYes

Fingerprint

Growth Factor Receptors
Transforming Growth Factors
Heart Atria
Atrial Fibrillation
Cardiac Electrophysiologic Techniques
Fibrosis
Dogs
Heart Failure
Electroporation
Canidae
Plasmids
Gene Expression
Injections

Keywords

  • atrial fibrillation
  • electroporation
  • fibrosis
  • gene therapy
  • heart failure

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Constitutive expression of a dominant-negative TGF-β type II receptor in the posterior left atrium leads to beneficial remodeling of atrial fibrillation substrate. / Kunamalla, Aaron; Ng, Jason; Parini, Vamsi; Yoo, Shin; Mcgee, Kate A.; Tomson, Todd T.; Gordon, David; Thorp, Edward B.; Lomasney, Jon; Zhang, Qiang; Shah, Sanjiv; Browne, Suzanne; Knight, Bradley P.; Passman, Rod; Goldberger, Jeffrey; Aistrup, Gary; Arora, Rishi.

In: Circulation Research, Vol. 119, No. 1, 24.06.2016, p. 69-82.

Research output: Contribution to journalArticle

Kunamalla, A, Ng, J, Parini, V, Yoo, S, Mcgee, KA, Tomson, TT, Gordon, D, Thorp, EB, Lomasney, J, Zhang, Q, Shah, S, Browne, S, Knight, BP, Passman, R, Goldberger, J, Aistrup, G & Arora, R 2016, 'Constitutive expression of a dominant-negative TGF-β type II receptor in the posterior left atrium leads to beneficial remodeling of atrial fibrillation substrate', Circulation Research, vol. 119, no. 1, pp. 69-82. https://doi.org/10.1161/CIRCRESAHA.115.307878
Kunamalla, Aaron ; Ng, Jason ; Parini, Vamsi ; Yoo, Shin ; Mcgee, Kate A. ; Tomson, Todd T. ; Gordon, David ; Thorp, Edward B. ; Lomasney, Jon ; Zhang, Qiang ; Shah, Sanjiv ; Browne, Suzanne ; Knight, Bradley P. ; Passman, Rod ; Goldberger, Jeffrey ; Aistrup, Gary ; Arora, Rishi. / Constitutive expression of a dominant-negative TGF-β type II receptor in the posterior left atrium leads to beneficial remodeling of atrial fibrillation substrate. In: Circulation Research. 2016 ; Vol. 119, No. 1. pp. 69-82.
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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.",
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AU - Ng, Jason

AU - Parini, Vamsi

AU - Yoo, Shin

AU - Mcgee, Kate A.

AU - Tomson, Todd T.

AU - Gordon, David

AU - Thorp, Edward B.

AU - Lomasney, Jon

AU - Zhang, Qiang

AU - Shah, Sanjiv

AU - Browne, Suzanne

AU - Knight, Bradley P.

AU - Passman, Rod

AU - Goldberger, Jeffrey

AU - Aistrup, Gary

AU - Arora, Rishi

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N2 - 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.

AB - 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.

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KW - electroporation

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KW - gene therapy

KW - heart failure

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