Background:
Inhibiting late sodium current (I
NaL
) reduced drug-induced QTc prolongation in a recent clinical trial. Induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) have emerged as a valuable tool in preclinical assessment of multichannel blocking drugs’ potential to prolong QT and induce arrhythmias. However, sodium channels in commercially available iPSC-CMs are known to be under expressed, necessitating investigation into the presence and effects of I
NaL
in this electrophysiological model.
Methods and Results:
A platform combining simultaneous measurements of field potential and contraction (xCELLigence RTCA CardioECR, ACEA Biosciences) was used to assess the acute effects of three I
NaL
enhancing drugs, ATX-II, ibutilide, and alfuzosin, given alone or in combination with an I
NaL
blocker, lidocaine in iPSC-CMs (iCell Cardiomyocytes
2
, Cellular Dynamics). Additionally, dofetilide, diltiazem, and lidocaine alone were included as positive controls for hERG, L-type calcium, and sodium channel block.
ATX-II, a potent and specific I
NaL
enhancer, caused significant dose dependent rate-corrected field potential duration (FPDc) prolongation, which was then subsequently reduced in a dose dependent manner by the addition of lidocaine. At 100 nM ATX-II prolonged the FPDc by 1153.8 ± 135.8 ms from 360.5 ± 16.4 ms at the baseline, which was then reduced to 537 ± 37.4 ms with the addition of 30 μM lidocaine. Ibutilide (0.1-1 μM), a class III antiarrhythmic, caused beating rate decreases and early after depolarizations (EADs) that were not affected by lidocaine addition. Alfuzosin, which increases both peak and late sodium currents, caused dose-dependent reduction of beating rate, FPDc prolongation, and EADs at 5 μM and 10 μM. Alfuzosin-induced EADs were mitigated by addition of lidocaine (5-15 μM).
Conclusions:
Late sodium current enhancers prolonged repolarization and induced arrhythmias in human iPSC-CMs. These effects were reversed by addition of lidocaine, a specific late sodium current blocker. These results are consistent with the late sodium current being present in iPSC-CMs in the presence of a late sodium current enhancer, which may have implications for drug safety testing.
Extracellular Recordings of Patterned Human Pluripotent Stem Cell-Derived Cardiomyocytes on Aligned Fibers