Publications

@article{Saleem2020-kf,

title = {Blinded, multicenter evaluation of drug-induced changes in 

 contractility using human-induced pluripotent stem cell-derived 

 cardiomyocytes},

author = {Umber Saleem and Berend J Meer and Puspita A Katili and Nurul A N Mohd Yusof and Ingra Mannhardt and Ana Krotenberg Garcia and Leon Tertoolen and Tessa Korte and Maria L H Vlaming and Karen McGlynn and Jessica Nebel and Anthony Bahinski and Kate Harris and Eric Rossman and Xiaoping Xu and Francis L Burton and Godfrey L Smith and Peter Clements and Christine L Mummery and Thomas Eschenhagen and Arne Hansen and Chris Denning},

year  = {2020},

date = {2020-07-01},

journal = {Toxicol. Sci.},

volume = {176},

number = {1},

pages = {103\textendash123},

publisher = {Oxford University Press (OUP)},

abstract = {Animal models are 78% accurate in determining whether drugs 

 will alter contractility of the human heart. To evaluate the 

 suitability of human-induced pluripotent stem cell-derived 

 cardiomyocytes (hiPSC-CMs) for predictive safety pharmacology, 

 we quantified changes in contractility, voltage, and/or Ca2+ 

 handling in 2D monolayers or 3D engineered heart tissues (EHTs). 

 Protocols were unified via a drug training set, allowing 

 subsequent blinded multicenter evaluation of drugs with known 

 positive, negative, or neutral inotropic effects. Accuracy 

 ranged from 44% to 85% across the platform-cell 

 configurations, indicating the need to refine test conditions. 

 This was achieved by adopting approaches to reduce 

 signal-to-noise ratio, reduce spontaneous beat rate to $\leq$ 1 

 Hz or enable chronic testing, improving accuracy to 85% for 

 monolayers and 93% for EHTs. Contraction amplitude was a good 

 predictor of negative inotropes across all the platform-cell 

 configurations and of positive inotropes in the 3D EHTs. 

 Although contraction- and relaxation-time provided confirmatory 

 readouts forpositive inotropes in 3D EHTs, these parameters 

 typically served as the primary source of predictivity in 2D. 

 The reliance of these ``secondary'' parameters to inotropy in 

 the 2D systems was not automatically intuitive and may be a 

 quirk of hiPSC-CMs, hence require adaptations in interpreting 

 the data from this model system. Of the platform-cell 

 configurations, responses in EHTs aligned most closely to the 

 free therapeutic plasma concentration. This study adds to the 

 notion that hiPSC-CMs could add value to drug safety evaluation.},

keywords = {alternatives to animal testing, cardiomyocytes, contractility, CRACK-IT project, electrophysiology, human-induced   pluripotent stem cells, inotropy, predictive toxicology, safety   pharmacology},

pubstate = {published},

tppubtype = {article}

}