title: Overexpression of Kir2.1 channel in embryonic stem cell-derived cardiomyocytes attenuates posttransplantation proarrhythmic risk in myocardial infarction.
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.
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Song-Yan
authors.initials: SY
authors.lastname: Liao
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.forename: Yau-Chi
authors.initials: YC
authors.lastname: Chan
authors.forename: Pandora
authors.initials: P
authors.lastname: Mei-Chu Yip
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Li
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D004562:Electrocardiography / Q000379:methods; D053595:Embryonic Stem Cells / Q000637:transplantation*; D005786:Gene Expression Regulation; D016027:Heart Transplantation / Q000009:adverse effects* / Q000379:methods; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009203:Myocardial Infarction / Q000175:diagnosis / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D011183:Postoperative Complications / Q000175:diagnosis / Q000628:therapy; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000628:therapy*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying; D004318:Doxycycline