The action potential and comparative pharmacology of stem cell-derived human cardiomyocytes

Peng, Shengde; Lacerda, Antonio E.; Kirsch, Glenn E.; Brown, Arthur M.; Bruening‐Wright, Andrew

doi:10.1016/j.vascn.2010.01.014

Cited by 173 publications

(125 citation statements)

References 17 publications

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“…In order to evaluate the utility of hiPSC-CMs as a tool for detecting drug-induced electrophysiological modifications, the effects of various drugs and chemical compounds have been assessed on the action potential waveform of single hiPSC-CM (Gibson et al, 2014;Peng et al, 2010) as well as the field potential configuration of two-dimensional cell sheets of hiPSC-CMs (Harris et al, 2013;Mehta et al, 2013;Nakamura et al, 2014;Nozaki et al, 2014;Uesugi et al, 2014). Thus, hiPSC-CMs have been well recognized as a new strategy that can provide reliable information for predicting drug-induced repolarization delay in the human heart.…”

Section: Introductionmentioning

confidence: 99%

Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance

et al. 2017

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-In order to characterize human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets as a model for detecting drug-induced conduction disturbance, we examined their electrophysiological and electropharmacological properties by using the multi-electrode array system with a programmed electrical stimulation protocol. At pre-drug control, the conduction speed, effective refractory period and field potential duration were 0.14 ± 0.01 m/sec, 453 ± 10 msec and 361 ± 9 msec, respectively at a cycle length of 1,000 msec (n = 18). Shortening the pacing cycle length from 1,000 to 600 msec decreased the conduction speed and field potential duration, but prolonged the effective refractory period. Disopyramide, lidocaine and flecainide decreased the conduction speed but prolonged the effective refractory period and field potential duration, whereas the reverse was true for verapamil. Thus, conduction properties of the cell sheet may largely depend on the extent of Na + channel availability as is the case in the human ventricle. Importantly, there was no relationship between the conduction delay and 1 st spike amplitude reduction after the treatment of Na + channel blockers. These findings may provide crucial guide on future application of this new technology for early phase safety pharmacological screening of new chemical entities.

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Section: Introductionmentioning

confidence: 99%

Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance

et al. 2017

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“…Unfortunately, the stem cell-derived cardiomyocytes developed to date fail to faithfully replicate all of the electrophysiological properties of adult human cardiomyocytes displaying embryonic-like characteristics with altered numbers and types of ion channels. [7][8][9] Therefore, detailed biophysical and pharmacological analysis of individual ion channels in these cells will be a necessary prerequisite before their routine incorporation into the drug development process. We have previously undertaken a detailed pharmacological study of the L-type Ca 2 + channel in stem cellderived cardiomyocytes.…”

Section: Introductionmentioning

confidence: 99%

L-Type Ca²⁺ Channel Responses to Bay K 8644 in Stem Cell-Derived Cardiomyocytes Are Unusually Dependent on Holding Potential and Charge Carrier

Kang²,

Rampe³

2014

ASSAY and Drug Development Technologies

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Human stem cell-derived cardiomyocytes provide a cellular model for the study of electrophysiology in the human heart and are finding a niche in the field of safety pharmacology for predicting proarrhythmia. The cardiac L-type Ca 2+ channel is an important target for some of these safety studies. However, the pharmacology of this channel in these cells is altered compared to native cardiac tissue, specifically in its sensitivity to the Ca 2+ channel activator S-( -)-Bay K 8644. Using patch clamp electrophysiology, we examined the effects of S-( -)-Bay K 8644 in three separate stem cell-derived cardiomyocyte cell lines under various conditions in an effort to detect more typical responses to the drug. S-( -)-Bay K 8644 failed to produce characteristically large increases in current when cells were held at -40 mV and Ca 2+ was used as the charge carrier, although high-affinity binding and the effects of the antagonist isomer, R-(+)-Bay K 8644, were intact. Dephosphorylation of the channel with acetylcholine failed to restore the sensitivity of the channel to the drug. Only when the holding potential was shifted to a more hyperpolarized ( -60 mV) level, and external Ca 2+ was replaced by Ba 2+ , could large increases in current amplitude be observed. Even under these conditions, increases in current amplitude varied dramatically between different cell lines and channel kinetics following drug addition were generally atypical. The results indicate that the pharmacology of S-( -)-Bay K 8644 in stem cell-derived cardiomyocytes varies by cell type, is unusually dependent on holding potential and charge carrier, and is different from that observed in primary human heart cells.

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“…As an alternative to the comparison of the drug effects with published results from other laboratories, two recent studies have demonstrated concordance between hPSC-derived cardiomyocytes and conventional, well validated, rabbit and canine ex vivo Purkinje fiber models, which are commonly used as follow-up assays [15,16]. Using microelectrodes to measure the transmembrane action potential of hPSC-derived cardiomyocytes, Jonsson et al [15] determined parameters such as reverse use dependence, triangulation of the action potential, and short-term variability of repolarization to assess drug-induced arrhythmic events.…”

Section: Hpsc-derived Cardiomyocytes In Toxicity Testingmentioning

confidence: 99%

“…The results demonstrated that rabbit Purkinje fibers and ventricular-like hPSC-derived cardiomyocytes reacted in a similar way with regards to the incidence of early after-depolarization, increased triangulation, and short-term variability of repolarization in response to the human ether-à-go-go-related gene channel blocking compound E-4031. In a separate study, Peng et al [16] demonstrated that hPSC-derived cardiomyocytes used in an Figure 1. Frontloading of human relevant toxicity testing in preclinical drug discovery.…”

Section: Hpsc-derived Cardiomyocytes In Toxicity Testingmentioning

confidence: 99%

Concise Review: Human Pluripotent Stem Cell-Based Models for Cardiac and Hepatic Toxicity Assessment

Sartipy¹,

Björquist²

2011

Stem Cells

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Considering the costs associated with drug development, there are billions of dollars to be saved by reducing latestage attrition in the pharmaceutical industries. Reports on the use of human pluripotent stem cells (hPSCs) and their functional derivatives in applications for safety assessment of drugs have begun to appear in the scientific literature. These reports are encouraging and fuel further developments of improved human cellular models that may increase the clinical relevance and reduce the need of experimental animals in preclinical drug discovery. However, a few factors still limit the general and wide-spread industry implementation of these new stem cell-based models, including cost of manufacture, level of functionality of the differentiated cells, assay validation, verification of human relevance, and benchmarking to conventional models. This review discusses the emerging field of hPSCbased models for drug discovery and development with a focus on cardiac and hepatic toxicity testing and how these approaches may improve current applications used in the pharmaceutical industry. Although much research remains to make hPSC-based models mainstream tools in the industry, importantly, this review highlights currently available opportunities. In addition, a forward looking discussion on novel applications using tissue preparations generated from hPSCs illustrates the opportunities to create complex models in vitro with the aim of simulating the systemic response of a drug in vivo. STEM CELLS 2011;29:744-748 Disclosure of potential conflicts of interest is found at the end of this article.

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The action potential and comparative pharmacology of stem cell-derived human cardiomyocytes

Cited by 173 publications

References 17 publications

Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance

Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance

L-Type Ca²⁺ Channel Responses to Bay K 8644 in Stem Cell-Derived Cardiomyocytes Are Unusually Dependent on Holding Potential and Charge Carrier

Concise Review: Human Pluripotent Stem Cell-Based Models for Cardiac and Hepatic Toxicity Assessment

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The action potential and comparative pharmacology of stem cell-derived human cardiomyocytes

Cited by 173 publications

References 17 publications

Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance

Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance

L-Type Ca2+ Channel Responses to Bay K 8644 in Stem Cell-Derived Cardiomyocytes Are Unusually Dependent on Holding Potential and Charge Carrier

Concise Review: Human Pluripotent Stem Cell-Based Models for Cardiac and Hepatic Toxicity Assessment

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L-Type Ca²⁺ Channel Responses to Bay K 8644 in Stem Cell-Derived Cardiomyocytes Are Unusually Dependent on Holding Potential and Charge Carrier