Cardiotoxicity Assessment of Drugs Using Human iPS Cell-Derived Cardiomyocytes: Toward Proarrhythmic Risk and Cardio-Oncology

Abstract

: Growing evidence suggests that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used as a new human cell-based platform to assess cardiac toxicity/safety during drug development. Cardiotoxicity assessment is highly challenging due to species differences and various toxicities, such as electrophysiological and contractile toxicities, which can result in proarrhythmia and heart failure. To explore proarrhythmia risk, the multi-electrode array (MEA) platform is widely used to assess QT-interval prolongation and the proarrhythmic potential of drug candidates using hiPSC-CMs. Several consortiums, including the Comprehensive in vitro Proarrhythmia Assay (CiPA) and the Japanese iPS Cardiac Safety Assessment (JiCSA) have demonstrated the applicability of hiPSC-CMs/MEA for assessing the torsadogenic potential of drug candidates. Additionally, contractility is a key safety issue in drug development, and efforts have been undertaken to measure contractility by a variety of imaging-based methods using iPS-CMs. Therefore, hiPSC-CMs might represent a standard testing tool for evaluating proarrhythmic and contractile potentials. This review provides new insights into the practical application of hiPSC-CMs in early or late-stage non-clinical testing during drug development.

Functional isolation, culture and cryopreservation of adult human primary cardiomyocytes

“…With the advent of induced pluripotent stem cell technology, human somatic cell-derived cardiomyocytes have gained popularity due to its elimination of species differences and the possibility of performing large-scale in vitro experiments. 60 Nowadays, the drug-induced pro-arrhythmic risk is frequently evaluated by in silico modeling or by using stem cell-derived cardiomyocytes, 61 the latter of which exhibit an immature phenotype, and can sometimes generate false-positive predictions of Torsades de Pointe (TdP) risks. 62 Adult hPCMs, by contrast, possess all native physiological and pharmacological properties and therefore can overcome many of the inherent limitations of current models.…”

hiPSCs Derived Cardiac Cells for Drug and Toxicity Screening and Disease Modeling: What Micro- Electrode-Array Analyses Can Tell Us

“…Cardiomyocytes generated from human iPSCs are used to study heart development, cardiac function and heart diseases, and to develop novel pharmacological therapeutics [11,21,23,134]. This involves a detailed electrophysiological characterization of these cardiomyocytes under physiological and pathological conditions.…”

Virulence factors released from Porphyromonas gingivalis induce electrophysiological dysfunction in human pluripotent stem cell-derived cardiomyocytes

“…hESC-CMs have been demonstrated to be a good alternative for cardiac disease modeling, drug screening, and cardiotoxicity testing, as they are known to have electrophysiological properties similar to those of native cardiomyocytes. 17 , 18 In this study, we investigated the effects of Pg culture broth on the survival, electrophysiological properties, and transcriptional activity of hESC-CMs to ascertain the association between periodontopathogenic bacteria and cardiac arrhythmia.…”