The cardiac action potential (CAP) of stem cell-derived human cardiomyocytes (SC-hCMs)
is potentially the most powerful preclinical biomarker for cardiac safety and efficacy
in humans. Our experiments tested this hypothesis by examining the CAP and relevant
pharmacology of these cells.
The electrophysiological and pharmacological profiles of SC-hCMs were compared to
rabbit and canine Purkinje fibers (PFs). Ventricular SC-hCMs provided the dominant
electrophysiological phenotype (approximately 82%) in a population of ventricular,
atrial and nodal cardiomyocytes (CMs). The effects of reference compounds were measured
in SC-hCMs using perforated patch, current clamp recording. Selective inhibitors of
I(Kr), I(Ks), I(Ca,L), and I(Na), and norepinephrine (NE), were tested on SC-hCM action
potentials (APs).
AP prolongation was observed upon exposure to hERG channel blockers (terfenadine,
quinidine, cisapride, sotalol, E-4031 and verapamil), with significantly shorter latencies
than in PF assays. For the torsadogenic compounds, terfenadine and quinidine, SC-hCM
AP prolongation occurred at significantly lower concentrations than in canine or rabbit
PF APs. Moreover, the I(Ks) blocker chromanol 293B prolonged APs from SC-hCMs, whereas
both rabbit and canine PF assays are insensitive to I(Ks) blockers in the absence
of adrenergic preconditioning. Early afterdepolarizations (EADs) were induced by 100
nM E-4031 and 100 nM cisapride in the SC-hCM assay, but not in the canine or rabbit
PF assay. Selective inhibition of I(Na) and I(Ca,L) slowed V(max) and shortened AP
duration, respectively. NE prolonged the AP duration of SC-hCMs.
The CAP of SC-hCMs has been validated as a powerful preclinical biomarker for cardiac
safety and efficacy. In addition to its human nature, the SC-hCM AP assay removes
diffusion delays, reduces test compound consumption, demonstrates an overall pharmacological
sensitivity that is greater than conventional rabbit or canine PF assays, and accurately
predicts cardiac risk of known torsadogenic compounds.
2010 Elsevier Inc. All rights reserved.