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

• Published in: Nature communications Vol. 10; no. 1; pp. 4325 - 9
• Main Authors: van Meer, Berend J., Krotenberg, Ana, Sala, Luca, Davis, Richard P., Eschenhagen, Thomas, Denning, Chris, Tertoolen, Leon G. J., Mummery, Christine L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.09.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 14; 14/34; 14/63; 49; 59; 631/114/2397; 631/1647/1888/1493; 631/1647/245/2226; 631/532/2064/2158; 9/10; Action potential; Action Potentials; Algorithms; Calcium; Calcium - metabolism; Cardiomyocytes; Computational Biology; Contraction; Coupling; Excitation; Excitation-contraction coupling; Fluorescence; Fluorescent Dyes; Heart; Human behavior; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Ion Channels; multidisciplinary; Multiplexing; Muscle contraction; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Optical Imaging; Parameter identification; Pluripotency; Science; Science (multidisciplinary); Sensitivity; Statistical analysis; Stem cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12354-8

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. Cardiomyocytes obtained from human induced pluripotent stem cells are increasingly used for drug testing, but they are not always predictive of the heart contractile responses. Here the authors develop a method to measure cytosolic calcium, action potentials and contraction simultaneously, to achieve higher sensitivity for drug screenings.