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Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes in the Evaluation of Cardiotoxic Potential of Drugs

  • Yee Xiang Chang
  • Christine L. Mummery
Chapter

Abstract

Drug development process is currently a lengthy and costly process. One contributing factor to the high cost of drugs is the expense of failed products. To address this problem, early detection of potentially harmful drugs is important so that their development does not advance into expensive clinical trials and then fail to get regulatory approval. Drugs that cause heart damage are among those most commonly removed from the market. Current in vitro safety pharmacology screenings only focus on the evaluation of drug-induced QT prolongation or torsade des pointes (TdP) risks by examining individual cardiac ion channel currents or the action potential. These screenings are oversimplified, resulting in inaccurate prediction, high drug attrition rates, and drug withdrawals from the market. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are promising models for cardiotoxicity screening as some human cardiomyocyte features are recapitulated and disease- and patient-specific lines can be generated. The new generation of iPSCs has solved the problem of inefficient cardiomyocyte differentiation and provides optimism in the application of hiPSC-CMs in cardiotoxicity screening. In this chapter, an overview is given of safety pharmacological assays evaluating hiPSC-CM function, and the validity of the application of hiPSC-CM models in cardiotoxicity screening will be assessed.

Keywords

Human pluripotent stem cells Cardiomyocyte differentiation Cardiac disease Drug discovery Cardiac arrhythmia 

Abbreviations

AP

Action potential

APA

Action potential amplitude

APD

Action potential duration

CM

Cardiomyocyte

CSD

Calcium-sensitive detector

EC50

Half maximal effective concentration

ECAR

Extracellular acidification rate

ECG

Electrocardiogram

EHT

Engineered heart tissue

ESC

Embryonic stem cell

FDA

Food and Drug Administration

FP

Field potential

FPA

Field potential amplitude

FPD

Field potential duration

HEK-293 cells

Human embryonic kidney 293 cells

hERG

Human Ether-à-go-go-Related Gene

hiPSC-CM

Human-induced pluripotent stem cell-derived cardiomyocyte

IC50

Half maximal inhibition concentration

ICH

The International Council on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

IKr

Inward-rectifier K+ current

iPSC

Induced pluripotent stem cell

ISI

Interspike interval

MEA

Multielectrode arrays

NCE

New chemical entities

OCR

Oxygen consumption rate

TdP

Torsade de pointes

Vmax

Maximal upstroke velocity

VSD

Voltage-sensitive dye

XF

Extracellular flux

Notes

Acknowledgments

We thank Dr. Joost O. Fledderus from the University Medical Center Utrecht for his expertise and comments that improved the manuscript. In addition, we apologize to all those authors whose excellent work could not be cited due to space restrictions.

Disclosures

C.L.M. is a cofounder of Pluriomics B.V.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.University of UtrechtUtrechtThe Netherlands
  2. 2.Department of Anatomy and EmbryologyLeiden University Medical CentreLeidenThe Netherlands

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