Abstract | BACKGROUND: Cellular replacement strategies using embryonic stem cell-derived cardiomyocytes (ESC-CMs) have been shown to improve left ventricular (LV) ejection fraction and prevent LV remodeling post- myocardial infarction (MI). Nonetheless, the immature electrical phenotypes of ESC-CMs may increase the risk of ventricular tachyarrhythmias (VTs) and sudden death. OBJECTIVE: To investigate whether the forced expression of Kir2.1-encoded inward rectifying K(+) channels that are otherwise absent in ESC-CMs would attenuate their proarrhythmic risk after transplantation post-MI. METHODS: Mouse ESC line stably transduced with a lentivirus (LentV)-based doxycycline (DOX)-inducible system coexpressing the transgenes Kir2.1 and a dsRed (LentV-THM-Kir2.1-GFP/LentV-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 after transplantation. RESULTS: ESC-CM DOX(+) with atrial and ventricular phenotype exhibited more hyperpolarizing resting membrane potential than did ESC-CM DOX(-) (P< .05). Transplantations of ESC-CM DOX(-) and ESC-CM DOX(+) both significantly improved LV ejection fraction, LV end-systolic diameter, end-systolic pressure-volume relationship, and positive maximal and negative pressure derivative (P< .05) at 4 weeks compared with the MI group; however, the DOX(-) group (22 of 40, 55%) had a significantly higher early sudden death rate than the DOX(+) group (13 of 40, 32.5%; P = .036). Telemetry monitoring revealed that the DOX(-) group (6.09%±3.65%) had significantly more episodes of spontaneous VT compared with the DOX(+) group (0.92%±0.81%; P< .05). In vivo programmed electrical stimulation at 2 weeks resulted in a significantly higher incidence of inducible VT in the DOX(-) group (9 of 16, 56.25%) compared with the DOX(+) group (3 of 16, 18.75%; P = .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.
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Authors | Song-Yan Liao, Hung-Fat Tse, Yau-Chi Chan, Pandora Mei-Chu Yip, Yuelin Zhang, Yuan Liu, Ronald A Li |
Journal | Heart rhythm
(Heart Rhythm)
Vol. 10
Issue 2
Pg. 273-82
(Feb 2013)
ISSN: 1556-3871 [Electronic] United States |
PMID | 23041574
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Kir2.1 channel
- Potassium Channels, Inwardly Rectifying
- Doxycycline
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Topics |
- Animals
- Cells, Cultured
- Disease Models, Animal
- Doxycycline
(pharmacology)
- Electrocardiography
(methods)
- Embryonic Stem Cells
(transplantation)
- Gene Expression Regulation
- Heart Transplantation
(adverse effects, methods)
- Immunohistochemistry
- Male
- Mice
- Mice, Inbred Strains
- Myocardial Infarction
(diagnosis, therapy)
- Myocytes, Cardiac
(metabolism)
- Phenotype
- Postoperative Complications
(diagnosis, therapy)
- Potassium Channels, Inwardly Rectifying
(genetics, metabolism)
- Risk Assessment
- Sensitivity and Specificity
- Tachycardia, Ventricular
(etiology, therapy)
- Ventricular Remodeling
(physiology)
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