Simultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes

Berend J. Meer, Ana Krotenberg, Luca Sala, Richard P. Davis, Thomas Eschenhagen, Chris Denning, Leon G. J. Tertoolen and Christine L. Mummery ()
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Berend J. Meer: Leiden University Medical Center
Ana Krotenberg: Leiden University Medical Center
Luca Sala: Leiden University Medical Center
Richard P. Davis: Leiden University Medical Center
Thomas Eschenhagen: University Medical Center Hamburg Eppendorf
Chris Denning: University of Nottingham, University Park
Leon G. J. Tertoolen: Leiden University Medical Center
Christine L. Mummery: Leiden University Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) are increasingly recognized as valuable for determining the effects of drugs on ion channels but they do not always accurately predict contractile responses of the human heart. This is in part attributable to their immaturity but the sensitivity of measurement tools may also be limiting. Measuring action potential, calcium flux or contraction individually misses critical information that is captured when interrogating the complete excitation-contraction coupling cascade simultaneously. Here, we develop an hypothesis-based statistical algorithm that identifies mechanisms of action. We design and build a high-speed optical system to measure action potential, cytosolic calcium and contraction simultaneously using fluorescent sensors. These measurements are automatically processed, quantified and then assessed by the algorithm. Multiplexing these three critical physical features of hiPSC-CMs allows identification of all major drug classes affecting contractility with detection sensitivities higher than individual measurement of action potential, cytosolic calcium or contraction.

Date: 2019
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DOI: 10.1038/s41467-019-12354-8

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