Proarrhythmic risk of embryonic stem cell-derived cardiomyocyte transplantation in infarcted myocardium.
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.
Liao
Song-Yan
SY
Cardiology Division, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, Hong Kong Special Administrative Region, China.
Liu
Yuan
Y
Siu
Chung-Wah
CW
Zhang
Yuelin
Y
Lai
Wing-Hon
WH
Au
Ka-Wing
KW
Lee
Yee-Ki
YK
Chan
Yau-Chi
YC
Yip
Pandora Mei-Chu
PM
Wu
Ed X
EX
Wu
Yin
Y
Lau
Chu-Pak
CP
Li
Ronald A
RA
Tse
Hung-Fat
HF
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
D049452:Green Fluorescent Proteins