title: Proarrhythmic risk of embryonic stem cell-derived cardiomyocyte transplantation in infarcted myocardium.
abstract: BACKGROUND
  Cellular replacement strategies using embryonic stem cells (ESCs) and their cardiac derivatives are emerging as novel experimental therapeutic paradigms for the treatment of post-myocardial infarction (MI) left ventricular (LV) dysfunction; however, their potential proarrhythmic risk remains unclear.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the functional effect and proarrhythmic risk of ESC transplantation in a mouse model of MI.
  
  
  METHODS
  We compared the functional effects and proarrhythmic risk of direct intramyocardial transplantation of 3 × 10(5) undifferentiated mouse ESCs (MI+ESC group, n = 33) and mouse ESC-derived cardiomyocytes (MI+ESC-CM group, n = 40) versus culture medium (MI group, n = 33) at the infarct border zone in a mouse model of acute MI. LV performance was assessed with serial cardiac magnetic resonance imaging (MRI) at 1 and 3 week(s) post-MI, and invasive LV pressure measurement was assessed (dP/dt) at 4 weeks before sacrifice for histological examination. Furthermore, electrophysiological study was also performed in another set of animals in each group (n = 24) to assess for proarrhythmias after transplantation.
  
  
  RESULTS
  In vitro cellular electrophysiological study demonstrated that ESC-CMs exhibit arrhythmogenesis including automaticity, lengthened action potential duration, and depolarized resting membrane potential. At 4 weeks, the MI+ESC-CM group (21/40, 53%) had a higher mortality rate compared with those in the MI group (10/33, 30%, P = .08) and in the MI+ESC group (7/33, 21%, P = .012). Electrophysiological study showed a significantly higher incidence of inducible ventricular tachyarrhythmias in the MI+ESC-CM group (13/24, 54%) compared with in the MI group (6/24, 21%, P = .039) and in the MI+ESC group (5/24, 21%, P = .017). Cardiac MRI showed similar improvement in LV ejection fraction in the MI+ESC and MI+ESC-CM groups compared with in the MI group at 1 week (27.5% ± 3.8%; 30.3% ± 5.2% vs. 12.4% ± 1.4%; P < .05) and 3 weeks (29.8% ± 3.9%; 27.0% ± 4.8% vs. 10.6% ± 2.8%; P < .05) post-MI, respectively. Furthermore, invasive hemodynamic assessment at 4 weeks showed significant similar improvement in LV +dP/dt in the MI+ESC (2,644 ± 391 mmHg/s, P < .05) and MI+ESC-CM groups (2,539 ± 389 mmHg/s; P < .05) compared with in the MI group (2,042 ± 406 mmHg/s).
  
  
  CONCLUSIONS
  Our results demonstrate that transplantation of undifferentiated ESCs and ESC-CMs provides similar improvement in cardiac function post-MI. However, transplantation of ESC-CMs is associated with a significantly higher prevalence of inducible ventricular tachyarrhythmias and early mortality than transplantations with ESCs.
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Song-Yan
authors.initials: SY
authors.lastname: Liao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Chung-Wah
authors.initials: CW
authors.lastname: Siu
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wing-Hon
authors.initials: WH
authors.lastname: Lai
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Au
authors.forename: Yee-Ki
authors.initials: YK
authors.lastname: Lee
authors.forename: Yau-Chi
authors.initials: YC
authors.lastname: Chan
authors.forename: Pandora Mei-Chu
authors.initials: PM
authors.lastname: Yip
authors.forename: Ed X
authors.initials: EX
authors.lastname: Wu
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
authors.forename: Chu-Pak
authors.initials: CP
authors.lastname: Lau
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Li
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002454:Cell Differentiation; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D053595:Embryonic Stem Cells / Q000637:transplantation*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019028:Magnetic Resonance Imaging, Cine; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000637:transplantation*; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D018487:Ventricular Dysfunction, Left / Q000601:surgery; D017725:Ventricular Pressure
chemical_list: D049452:Green Fluorescent Proteins