Evolution of strategies to improve preclinical cardiac safety testing

Gintant, Gary A.; Sager, Philip T.; Stockbridge, Norman

doi:10.1038/nrd.2015.34

Cited by 349 publications

(260 citation statements)

References 163 publications

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“…The resulting contractile and electrical dysfunction often leads to abnormal heartbeat and life‐threatening arrhythmias (Ewer and Ewer, 2015; Gintant et al , 2016). Arrhythmia is currently an immense burden on public health, with millions of people at risk of heart malfunction because of the cardiotoxic effects of drugs (Rubinstein and Camm, 2002; Vejpongsa and Yeh, 2014; Viskin et al , 2015).…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…We next assessed the effects of verapamil and paracetamol, which were found to have no effects on human ventricular repolarization, consistent with the known lack of proarrhythmic risk posed by these drugs (Gintant, Sager, & Stockbridge, 2016;Lawrence, Bridgland-Taylor, Pollard, Hammond, & Valentin, 2006;Redfern et al, 2003). Our APD data from healthy donor hearts showed that while paracetamol caused no change in APD (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…Therefore, drug action as a function of pacing rate in the human heart warrants further assessment. Dofetilide, d,l-sotalol and quinidine have been associated with pro-arrhythmic risk (Frommeyer & Eckardt, 2016;Gintant, Sager, & Stockbridge, 2016;Redfern et al, 2003). Human trabeculae yielded information about the ability of dofetilide (Fig.…”

Section: Discussionmentioning

confidence: 99%

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

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While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced proarrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

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“…Contractility is a major pre-clinical and clinical parameter to assess normal and deficient contractile performance of the heart [46]. The RLFI system was thus evaluated as a platform to detect drug-induced effects on contractility.…”

Section: Evaluation Of the Inotropic Effects Of Blebbistatinmentioning

confidence: 99%

Reflective lens-free imaging on high-density silicon microelectrode arrays for monitoring and evaluation of in vitro cardiac contractility

Pauwelyn

Stahl

Mayo

et al. 2018

Biomed. Opt. Express

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Abstract:The high rate of drug attrition caused by cardiotoxicity is a major challenge for drug development. Here, we developed a reflective lens-free imaging (RLFI) approach to non-invasively record in vitro cell deformation in cardiac monolayers with high temporal (169 fps) and non-reconstructed spatial resolution (352 µm) over a field-of-view of maximally 57 mm 2 . The method is compatible with opaque surfaces and silicon-based devices. Further, we demonstrated that the system can detect the impairment of both contractility and fast excitation waves in cardiac monolayers. Additionally, the RLFI device was implemented on a CMOS-based microelectrode array to retrieve multi-parametric information of cardiac cells, thereby offering more in-depth analysis of drug-induced (cardiomyopathic) effects for preclinical cardiotoxicity screening applications.

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Evolution of strategies to improve preclinical cardiac safety testing

Cited by 349 publications

References 163 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?

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Reflective lens-free imaging on high-density silicon microelectrode arrays for monitoring and evaluation of in vitro cardiac contractility

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