Document Detail


Over-expression of Kir2.1 Channel in Embryonic Stem Cell-Derived Cardiomyocytes Attenuates Post-Transplantation Proarrhythmic Risk in Myocardial Infarction.
MedLine Citation:
PMID:  23041574     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: Cellular replacement strategies using embryonic stem cell-derived cardiomyocytes (ESC-CMs) have been shown to improve left ventricular (LV) ejection fraction (LVEF) and prevent LV remodelling post-myocardial infarction (MI). Nonetheless the immature electrical phenotypes of ESC-CMs may increase the risk of ventricular tachyarrhythmias (VT) and sudden death. OBJECTIVE: This study investigated whether forced expression of Kir2.1-encoded inward rectifying K(+) channels that are otherwise absent in ESC-CMs would attenuate their proarrhythmic risk after post-MI transplantation. METHODS: Mouse ESC line stably transduced with a lentivirus (LV)-based doxycycline (DOX)-inducible system co-expressing the transgenes Kir2.1 and a dsRed (LV-THM-Kir2.1-GFP/LV-TR-KRAB-dsRed) was differentiated into ESC-CMs with (DOX+) or without (DOX-) treatment with DOX. Detailed in-vitro and in-vivo assessments of LV function and cardiac electrophysiology were measured 4 weeks following transplantation. RESULTS: ESC-CMs DOX+ with atrial and ventricular phenotype exhibited more hyperpolarizing resting membrane potential than ESC-CM DOX- (P<0.05). Transplantations of ESC-CMs DOX- and ESC-CMs DOX+ both significantly improved LVEF,LVIDs, ESPVR and +dP/dt (P<0.05) at 4 weeks compared with the MI group, however, the DOX- group (22/40, 55%) had a significantly higher early sudden death rate than the DOX+ group (13/40, 32.5%; P=0.036). Telemetry monitoring revealed that the DOX- group (6.09%±3.65%) had significantly more episodes of spontaneous VT compared with DOX+ group (0.92%±0.81 P<0.05). In-vivo programmed electrical stimulation at 2 weeks resulted in a significantly higher incidence of inducible VT in the DOX- group (9/16, 56.25%) compared with the DOX+ group (3/16, 18.75%; P=0.031). CONCLUSIONS: Forced expression of Kir2.1 in ESC-CMs improves their electrical phenotypes and lowers the risk of inducible and spontaneous VT after post-MI transplantation.
Authors:
Song-Yan Liao; Hung-Fat Tse; Yau-Chi Chan; Pandora Mei-Chu Yip; Yuelin Zhang; Yuan Liu; Ronald A Li
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-4
Journal Detail:
Title:  Heart rhythm : the official journal of the Heart Rhythm Society     Volume:  -     ISSN:  1556-3871     ISO Abbreviation:  Heart Rhythm     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101200317     Medline TA:  Heart Rhythm     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Inc.
Affiliation:
Cardiology Division, Department of Medicine, Queen Mary Hospital; The University of Hong Kong, Hong Kong, HKSAR, China;; Bengbu Medical College, Bengbu, China;
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