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 × 10⁵ 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.

Keywords: Embryonic stem cells, Cardiomyocytes, Myocardial infarction, Proarrhythmias

Abbreviations: CM, cardiomyocyte, ESC, embryonic stem cell, GFP, green fluorescent protein, H&E, hematoxylin and eosin, LV, left ventricular, LVEF, left ventricular injection fraction, MI, myocardial infarction, MRI, magnetic resonance imaging, TUNEL, terminal deoxynucleotidyl nick end labeling, VT, ventricular tachyarrhythmia