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HCN2/SkM1 Gene Transfer Into Canine Left Bundle Branch Induces Stable, Autonomically Responsive Biological Pacing at Physiological Heart Rates.
MedLine Citation:
PMID:  23395072     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
OBJECTIVES: This study sought to test the hypothesis that hyperpolarization-activated cyclic nucleotide-gated (HCN)-based biological pacing might be improved significantly by hyperpolarizing the action potential (AP) threshold via coexpression of the skeletal muscle sodium channel 1 (SkM1). BACKGROUND: Gene-based biological pacemakers display effective in vivo pacemaker function. However, approaches used to date have failed to manifest optimal pacemaker properties, defined as basal beating rates of 60 to 90 beats/min, a brisk autonomic response achieving maximal rates of 130 to 160 beats/min, and low to absent electronic backup pacing. METHODS: We implanted adenoviral SkM1, HCN2, or HCN2/SkM1 constructs into left bundle branches (LBB) or left ventricular (LV) epicardium of atrioventricular-blocked dogs. RESULTS: During stable peak gene expression on days 5 to 7, HCN2/SkM1 LBB-injected dogs showed highly stable in vivo pacemaker activity superior to SkM1 or HCN2 alone and superior to LV-implanted dogs with regard to beating rates (resting approximately 80 beats/min; maximum approximately 130 beats/min), no dependence on electronic backup pacing, and enhanced modulation of pacemaker function during circadian rhythm or epinephrine infusion. In vitro isolated LV of dogs overexpressing SkM1 manifested a significantly more negative AP threshold. CONCLUSIONS: LBB-injected HCN2/SkM1 potentially provides a more clinically suitable biological pacemaker strategy than other reported constructs. This superiority is attributable to the more negative AP threshold and injection into the LBB.
Authors:
Gerard J J Boink; Lian Duan; Bruce D Nearing; Iryna N Shlapakova; Eugene A Sosunov; Evgeny P Anyukhovsky; Eugene Bobkov; Yelena Kryukova; Nazira Ozgen; Peter Danilo; Ira S Cohen; Richard L Verrier; Richard B Robinson; Michael R Rosen
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-2-1
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  -     ISSN:  1558-3597     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-2-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Affiliation:
Department of Pharmacology, Columbia University, New York, New York; Center for Molecular Therapeutics, Columbia University, New York, New York; Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands; Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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