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Overexpression of Kir2.1 channel in embryonic stem cell-derived cardiomyocytes attenuates posttransplantation proarrhythmic risk in myocardial infarction.

AbstractBACKGROUND:
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.
AuthorsSong-Yan Liao, Hung-Fat Tse, Yau-Chi Chan, Pandora Mei-Chu Yip, Yuelin Zhang, Yuan Liu, Ronald A Li
JournalHeart rhythm (Heart Rhythm) Vol. 10 Issue 2 Pg. 273-82 (Feb 2013) ISSN: 1556-3871 [Electronic] United States
PMID23041574 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Kir2.1 channel
  • Potassium Channels, Inwardly Rectifying
  • Doxycycline
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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