Comparative analysis of media effects on human induced pluripotent stem cell-derived cardiomyocytes in proarrhythmia risk assessment.

Published

Journal Article

INTRODUCTION: Cardiotoxicity assessment using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) forms a key component of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). A potentially impactful factor on iPSC-CM testing is the presence of serum in the experimental media. Generally, serum-free media is used to most accurately reproduce "free" drug concentration. However, caution is needed; drug solubility and cardiomyocyte electrophysiology could be affected by media formulation, potentially impacting interpretation of drug-induced effects. METHODS: Effects of 25 drugs on properties of spontaneous field potentials in iPSC-CMs were assayed using a high-throughput microelectrode array (MEA) in two media formulations: serum-containing and serum-free. Comparative analysis was conducted on rate-corrected field potential duration (FPDc) and prevalence of arrhythmic events. Further MEA experiments were conducted, varying percentages of serum as well as carbon substrate components. Comparative LC-MS/MS analysis was done on two compounds to evaluate drug concentrations. RESULTS: In serum-free media, 9 drugs prolonged FPDc. In serum-containing, 11 drugs prolonged FPDc. Eighteen drugs induced arrhythmias, 8 of these induced arrhythmias at lower concentrations in serum-containing media. At the highest non-arrhythmic concentrations, 13 of 25 drugs exhibited significant differences in FPDc prolongation/shortening between the media. Increasing fractions of serum in media yielded higher FPDc measurements. LC-MS/MS analysis of moxifloxacin and quinidine showed higher concentrations in serum-containing media. DISCUSSION: The present study highlights media formulation as an important consideration for cardiac safety testing with iPSC-CMs. Results described here suggest that media formulation influences both compound availability and baseline electrophysiological properties. Special attention should be paid to media for future iPSC-CM assays.

Full Text

Duke Authors

Cited Authors

  • Schocken, D; Stohlman, J; Vicente, J; Chan, D; Patel, D; Matta, MK; Patel, V; Brock, M; Millard, D; Ross, J; Strauss, DG; Blinova, K

Published Date

  • March 2018

Published In

Volume / Issue

  • 90 /

Start / End Page

  • 39 - 47

PubMed ID

  • 29155283

Pubmed Central ID

  • 29155283

Electronic International Standard Serial Number (EISSN)

  • 1873-488X

Digital Object Identifier (DOI)

  • 10.1016/j.vascn.2017.11.002

Language

  • eng

Conference Location

  • United States