Estimating the Risk of Drug-Induced Proarrhythmia Using Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Abstract

Improved in vitro systems for predicting drug-induced toxicity are needed in the pharmaceutical and biotechnology industries to decrease late-stage drug attrition. One unmet need is an early screen for cardiotoxicity, which accounts for about one third of safety-based withdrawn pharmaceuticals. Herein, the first published report of a high-throughput functional assay employing a monolayer of beating human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is described, detailing a model that accurately detects drug-induced cardiac abnormalities. Using 96-well plates with interdigitated electrode arrays that assess impedance, the rhythmic, synchronous contractions of the iPSC-CMs were detected. Treatment of the iPSC-CMs with 28 different compounds with known cardiac effects resulted in compound-specific changes in the beat rate and/or the amplitude of the impedance measurement. Changes in impedance for the compounds tested were comparable with the results from a related technology, electric field potential assessment obtained from microelectrode arrays. Using the results from the set of compounds, an index of drug-induced arrhythmias was calculated, enabling the determination of a drug's proarrhythmic potential. This system of interrogating human cardiac function in vitro opens new opportunities for predicting cardiac toxicity and studying cardiac biology.

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

“…The non-dividing cells must be kept in standard culture conditions for 2 -3 weeks before 3 Compounds decreasing frequency 11% -20% (n = 6) ordered alphabetically: benzydamine, dorzolamide, maprotiline, strychnine, tacrine, tropisetron. 4 Compounds decreasing frequency 6% -10% (n = 10) ordered alphabetically: aripiprazole, bumetanide, cyclosporine, granisetron, hydroxytacrine, mepyramine, mesoridazine, methiothepin, neostigmine, primaquine. 5 Compounds increasing frequency 11% -42% (n = 11) ordered alphabetically: bisacodyl, clozapine, cyproheptadine, disulfiram, estradiol, fenoldopam, fulvestrant, gestrinone, imiquimod, nelfinavir, phenamil, quinacrine, quinpirole.…”

“…Human induced pluripotent stem cells (hiPSC) can differentiate into functional cardiomyocytes [1] and bio-engineering technologies can produce and reliably supply large quantities of isolated cells that are Open Access J. Biomedical Science and Engineering highly enriched in functional cardiomyocytes, as evidenced by their phenotypic and electrophysiological characteristics, and that develop into spontaneously-beating syncytia in-vitro [2][3][4]. These hiPSC-derived cardiomyocytes (hiPSC-CM) are likely to provide an ideal source of human cells to generate models for drug development, particularly when questions arise regarding cardiac effects that may be seen when a drug is administered to humans.…”

“…The beating rate of hiPSC-CM syncytia can be measured with high definition under physiological conditions using microelectrode arrays (MEA), which measure field potentials, or using impedance-sensing, which measures mechanical movements [4]. These techniques can provide valuable and very detailed information on drug effects in addition to simple effects on beating rate but they are low-throughput and they do not permit testing thousands of compounds within practical time and budget constraints.…”

“…This HTS system can be integrated into standard automated platforms but it is limited by two practical issues. First, temperature control is suboptimal as evidenced by the beating rates of ~15 bpm compared to the 35 -55 bpm found in well-controlled environments [4]. Second, the acquisition frequency (8 Hz) is at the lower limit when trying to record accurately beating rates that can reach 120 bpm (2 Hz) under stimulated conditions and it is too low to extract additional information (e.g., slope or duration).…”

Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology

“…High throughput toxicity screening using human iPSC-derived cardiomyocytes has been reported Mohamet L et al . Alzheimer's disease modeling using iPS cells Neurons using electrode sensors to acquire oscillating impedance measurements to detect the contraction and relaxation or beating of iPSC-derived cardiomyocytes in a 96-well plate format [46] . Arrhythmia data obtained from iPSCderived cardiomyocytes treated with cardiac modulators was qualitatively comparable to results obtained from more traditional, low throughput microelectrode arrays in parallel experiments.…”