Abstract 12418: Over-Expression of Kir2.1 Channel in Embryonic Stem Cells Derived Cardiomyocytes Reduces Their Post-Transplantation Proarrhythmic Risk in Myocardial Infarction
Background: Cellular replacement strategies using embryonic stem cells derived cardiomycytes (ESC-CMs) have been shown to improve left ventricular (LV) ejection fraction (LVEF) and prevent LV remodelling post-myocardial infarction (MI). However, immature electrical phenotypes of ESC-CMs might lead to increase risk of ventricular tachyarrhythmias (VT) and sudden death. Here, we hypothesized that bioengineering ESC-CMs by over-expression of Kir2.1 channel reduces proarrhythmic risk after transplantation post-MI.
Methods: Doxycycline (DOX) inducible transgene co-expression of Kir2.1 and dsRed (LV-THM-Kir2.1-GFP/LV-TR-KRAB-dsRed) murine ESC line was differentiated into CMs with (DOX+) or without (DOX-) treatment of DOX. We compared the cellular electrophysiology (EP) of these CMs with patch clamping, and functional effects on LV function and proarrhythmic risk in mouse model of MI. After MI, direct intramyocardial transplantation of 9×105 DOX+ ESC-CMs or DOX- ESC-CMs versus culture medium (MI group) were performed. In-vivo assessment of LV function and EP were measured at 4 wks post MI.
Results: Both transplantation of DOX- and DOX+ ESC-CMs significantly improved LVEF (54.1%±10.5% & 50.7%± 9.4% vs. 40.4%±8.1%, P<0.05) and +dP/dt (2651±609mmHg/s & 2555±369 mmHg/s vs. 1958±358 mmHg/s P<0.05) at 4 wks as compared with MI group. Cellular EP data showed that DOX+exhibited more hyperpolarizing resting membrane potential than DOX-ESC-CMs (-77.9±0.8 mV, n=10 vs. -65.8±0.3 mV, p<0.01) and similar to adult mouse ventricular cardiomyocytes (-70.7±2.6 mV). At 4 wks after transplantation, DOX- group (22/40, 55%) had a significantly higher mortality than the DOX+ group (13/40, 32.5%; p=0.036). Telemetry monitoring showed that DOX- group (6.09%±3.65%) had higher number of episodes of spontaneous VT compared with DOX+ group (0.92%±0.81 p<0.05). In-vivo programmed electrical stimulation at 2 wks showed a significant higher incidence of inducible VT in the DOX- group (9/16, 56.25%) compared with the DOX+ group (3/16, 18.75%; p=0.031).
Conclusions: Over-expression of Kir2.1 channel improves the electrical phenotype of ESC-CM and confers a lower risk of inducible and spontaneous VT and sudden death after transplantation for post-MI cardiac repair.
- © 2011 by American Heart Association, Inc.