Inversion and computational maturation of drug response using human stem cell derived cardiomyocytes in microphysiological systems
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Key result
A computational framework successfully inverted optically obtained voltage and calcium waveforms from immature hiPSC-derived cardiomyocytes to identify specific drug-induced ion channel blockages and predict their effects on mature adult cardiomyocytes.
Why the study?
Cardiomyocytes differentiated from hiPSCs have variable and immature electrophysiological properties, yielding results significantly different from adult counterparts during drug screening.
Does computational inversion of voltage and calcium waveforms from immature hiPSC-CMs accurately predict drug-induced ion channel blockages in mature cardiomyocytes?
Population
Cardiomyocytes differentiated from human induced pluripotent stem cells in microphysiological systems
Design
Computational and experimental preclinical study
Authors
Discussion
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Implication
Supports computational drug screening with immature hiPSC-CMs; leaves open clinical translation and adult cardiomyocyte validation.
Structured PICO
Does computational inversion of voltage and calcium waveforms from immature hiPSC-CMs accurately predict drug-induced ion channel blockages in mature cardiomyocytes?
P
Population
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in microphysiological systems (MPS)
I
Intervention
Application of a computational inversion framework to optically obtained voltage and calcium waveforms, tested with Verapamil and Cisapride
C
Comparator
Control conditions (baseline measurements prior to drug exposure) and simulated data
O
Outcome
Identification of specific ion channel blockages (e.g., ICaL, IKr) and prediction of drug-induced changes in mature ventricular cellssurrogate
A novel computational framework can invert optical voltage and calcium measurements from immature hiPSC-CMs to accurately predict drug-induced ion channel blockages and side effects in mature human cardiomyocytes.
Limitations
- Variability in hiPSC-CMs remains a challenge for batch to batch consistency.
- The voltage waveform cannot currently be imaged at the time resolution needed to obtain accurate measurements of the upstroke.
- Signal to noise ratio prevents adequate resolution of the plateau phase and the notch in the action potential, preventing inversion of the Ito current.
- The inversion algorithm is not able to correctly identify the block of smaller contributing currents like Ito and IKs.
- Cost function is largely insensitive to changes in minor currents like Ito and IKs
- Lack of uniqueness in determining conductances from action potential observations
Cite This Study
Tveito et al. (2018) studied Drug-induced cardiotoxicity (in vitro model). Computational maturation framework (in silico mapping of hiPSC-CMs) was evaluated on Identification of drug-induced ion channel blockages and prediction of mature action potential changes. A computational framework successfully inverted optically obtained voltage and calcium waveforms from immature hiPSC-derived cardiomyocytes to identify specific drug-induced ion channel blockages and predict their effects on mature adult cardiomyocytes.
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