A New System for Profiling Drug- Induced Calcium Signal Perturbation in Human Embryonic Stem Cell-Derived Cardiomyocytes
2015
The emergence of human stem cell–derived cardiomyocyte (hSCCM)–based assays in the cardiovascular (CV) drug discovery
sphere requires the development of improved systems for interrogating the rich information that these cell models have
the potential to yield. We developed a new analytical framework termed SALVO (synchronization, amplitude, length,
and variability of oscillation) to profile the amplitude and temporal patterning of intra- and intercellular calcium signals in
hSCCM. SALVO quantified drug-induced perturbations in the calcium signaling “fingerprint” in spontaneously contractile
hSCCM. Multiparametric SALVO outputs were integrated into a single index of in vitro cytotoxicity that confirmed the
rank order of perturbation as astemizole > thioridazine > cisapride > flecainide > valdecoxib > sotalol > nadolol ≈ control.
This rank order of drug-induced Ca2+ signal disruption is in close agreement with the known arrhythmogenic liabilities of
these compounds in humans. Validation of the system using a second set of compounds and hierarchical cluster analysis
demonstrated the utility of SALVO to discriminate drugs based on their mechanisms of action. We discuss the utility of this
new mechanistically agnostic system for the evaluation of in vitro drug cytotoxicity in hSCCM syncytia and the potential
placement of SALVO in the early stage drug screening framework.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
30
References
10
Citations
NaN
KQI