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

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

Content Provider	Semantic Scholar
Author	Kunamalla, Aaron Ng, Jason Parini, Vamsi Yoo, Shin Young McGee, Kate A. Tomson, Todd T. Gordon, David Thorp, Edward B. Lomasney, Jon W. Zhang, Qiang Shah, Sanjiv J. Browne, Suzanne Knight, Bradley P. Passman, Rod S. Goldberger, Jeffrey J. Aistrup, Gary L. Arora, Rishi
Copyright Year	2016
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.
Starting Page	69
Ending Page	82
Page Count	14
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://circres.ahajournals.org/content/circresaha/119/1/69.full.pdf?download=true
Alternate Webpage(s)	http://circresaha.smart01.highwire.org/content/circresaha/119/1/69.full.pdf?download=true
PubMed reference number	27217399v1
Alternate Webpage(s)	https://doi.org/10.1161/CIRCRESAHA.115.307878
DOI	10.1161/circresaha.115.307878
Journal	Circulation research
Volume Number	119
Issue Number	1
Language	English
Access Restriction	Open
Subject Keyword	Atrial Fibrillation Body tissue Canis familiaris Fc epsilon RI + RII Ab:ACnc:Pt:Ser:Qn Fibrosis Heart Atrium Heart failure LacZ Genes Left atrial structure N-(4-carboxyphenyl)retinamide Ventricular Fibrillation Ventricular Remodeling receptor
Content Type	Text
Resource Type	Article

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