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Assessment of extracellular field potential and Ca2+ transient signals for early QT/pro-arrhythmia detection using human induced pluripotent stem cell-derived cardiomyocytes

Overview of attention for article published in Journal of Pharmacological & Toxicological Methods, January 2017
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Title
Assessment of extracellular field potential and Ca2+ transient signals for early QT/pro-arrhythmia detection using human induced pluripotent stem cell-derived cardiomyocytes
Published in
Journal of Pharmacological & Toxicological Methods, January 2017
DOI 10.1016/j.vascn.2016.09.001
Pubmed ID
Authors

Najah Abi-Gerges, Amy Pointon, Karen L. Oldman, Martin R. Brown, Mark A. Pilling, Clare E. Sefton, Helen Garside, Christopher E. Pollard

Abstract

Cardiovascular toxicity is a prominent reason for failures in drug development, resulting in the demand for assays that can predict this liability in early drug discovery. We investigated whether iCell® cardiomyocytes have utility as an early QT/TdP screen. Thirty clinical drugs with known QT/TdP outcomes were evaluated blind using label-free microelectrode array (parameters measured were beating period (BP), field potential duration (FPD), fast Na(+) amplitude and slope) and live cell, fast kinetic fluorescent Ca(2+) transient FLIPR® Tetra (parameters measured were peak count, width, amplitude) systems. Many FPD-altering drugs also altered BP. Correction for BP, using a Log-Log (LL) model, was required to appropriately interpret direct drug effects on FPD. In comparison with human QT effects and when drug activity was to be predicted at top test concentration (TTC), LL-corrected FPD and peak count had poor assay sensitivity and specificity values: 13%/64% and 65%/11%, respectively. If effective free therapeutic plasma concentration (EFTPC) was used instead of TTC, the values were 0%/100% and 6%/100%, respectively. When compared to LL-corrected FPD and peak count, predictive values of uncorrected FPD, BP, width and amplitude were not much different. If pro-arrhythmic risk was to be predicted using Ca(2+) transient data, the values were 67%/100% and 78%/53% at EFTPC and TTC, respectively. Thus, iCell® cardiomyocytes have limited value as an integrated QT/TdP assay, highlighting the urgent need for improved experimental alternatives that may offer an accurate integrated cardiomyocyte safety model for supporting the development of new drugs without QT/TdP effects.

Mendeley readers

The data shown below were compiled from readership statistics for 47 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
France 1 2%
United States 1 2%
Unknown 45 96%

Demographic breakdown

Readers by professional status Count As %
Researcher 22 47%
Student > Ph. D. Student 10 21%
Student > Master 8 17%
Unspecified 2 4%
Other 2 4%
Other 3 6%
Readers by discipline Count As %
Medicine and Dentistry 8 17%
Engineering 7 15%
Biochemistry, Genetics and Molecular Biology 6 13%
Agricultural and Biological Sciences 6 13%
Pharmacology, Toxicology and Pharmaceutical Science 6 13%
Other 14 30%