MICE Models: Superior to the HERG Model in Predicting Torsade de Pointes

Kramer, James; Obejero‐Paz, Carlos A.; Myatt, Glenn J.; Kuryshev, Yuri A.; Bruening‐Wright, Andrew; Verducci, Joseph S.; Brown, Arthur M.

doi:10.1038/srep02100

Cited by 298 publications

(355 citation statements)

References 28 publications

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“…Immortalized mammalian cell lines such as HEK or CHO are genetically engineered to express K v 11.1 channels ectopically [or, better, combinations of selected ion channels as recently proposed in the MICE approach (Kramer et al , 2013)]. These assays are extensively used in the preclinical characterization of drugs because of low cost and flexibility.…”

Section: Cardiotoxicity Screening Methodologiesmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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Section: Cardiotoxicity Screening Methodologiesmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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“…Recent in silico modeling efforts have also concluded that the ratio of hERG to L-type Ca 2 + channel inhibition provides the best predictor of torsades de pointe in the clinic and highlights the notion that unintended inhibition of cardiac Ca 2 + channels may in some cases have a beneficial role for drug development/safety. 5 Recognizing this, the U.S. Food and Drug Administration has launched an initiative, whereby Ca 2 + channel screening, as part of a larger preclinical safety profile, will play a greater part in predicting the proarrhythmic potential for drugs in development. 6 Stem cell-derived cardiomyocytes represent a potential new tool to study cardiac ion channel pharmacology and are also expected to play an increasing role in drug development and safety testing in the future.…”

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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“…The subjects received a single dose of 400 mg quinidine sulfate (Watson Pharma, Corona, CA) or placebo under fasting conditions. Quinidine, not only blocks the hERG potassium channel, but also calcium and sodium channels at high concentrations [8].…”

Section: Protocolmentioning

confidence: 99%

Assessment of Spatial Heterogeneity of Ventricular Repolarization after Quinidine in Healthy Subjects

Corino¹,

Rivolta²,

Mainardi³

et al. 2017

Computing in Cardiology Conference (CinC)

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When spatial heterogeneity of ventricular repolarization (SHVR) increases, vulnerability to ventricular arrhythmias, including lethal ones, has also been observed to increase. Drug-induced multi-ion-channel blocks may increase SHVR. Aim of this study is to non-invasively assess whether quinidine, a strong hERG potassium channel blocker with weaker effects on calcium and late sodium currents, increases SHVR. We analyzed data from 21 healthy subjects that received both the drug and a placebo and underwent to 12 leads Holter monitoring. From the recording, three 10-s ECGs were extracted at each of 16 predefined time-points. SHVR was assessed by the Vindex, which evaluates the standard deviation of the repolarization times from multi-lead ECG recordings. At any time point, a value of V-index was computed for each of the three 10s ECGs and averaged if the difference in the mean RR of the 10s ECGs was lower than 50 ms. The Vindex did not change after the placebo (V-index pre-dose = 29.2 ± 9.9 ms vs. V-index post-dose1h = 26.7 ± 10.3, ns), whereas, after quinidine, it significantly increased one hour post-dose (V-index pre-dose = 29.5 ± 10.2 ms vs. Vindex post-dose1h = 46.5 ± 33.8 ms, p = 0.01). Quinidine had its maximum effect on the V-index 2.5 h after dose (V-index post-dose2.5h = 53.6 ± 39.6 ms).

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MICE Models: Superior to the HERG Model in Predicting Torsade de Pointes

Cited by 298 publications

References 28 publications

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

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

Assessment of Spatial Heterogeneity of Ventricular Repolarization after Quinidine in Healthy Subjects

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MICE Models: Superior to the HERG Model in Predicting Torsade de Pointes

Cited by 298 publications

References 28 publications

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

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

Assessment of Spatial Heterogeneity of Ventricular Repolarization after Quinidine in Healthy Subjects

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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