Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG

Jonsson, Malin K.B.; Vos, Marc A.; Mirams, Gary R.; Duker, Göran; Sartipy, Peter; Boer, Teun P. de; Veen, Toon A.B. van

doi:10.1016/j.yjmcc.2012.02.002

Cited by 130 publications

(92 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly and as suggested by others, GEVIs can be used in drug screens for arrhythmogenic potential. 14,43 In contrast to studies using voltage indicator dyes, GEVIs would also allow studies on chronic exposure to drugs or other stimuli.…”

Section: Discussionmentioning

confidence: 99%

Sensing Cardiac Electrical Activity With a Cardiac Myocyte–Targeted Optogenetic Voltage Indicator

Liao

Boer

Mutoh

et al. 2015

Circulation Research

Self Cite

View full text Add to dashboard Cite

Rationale: Monitoring and controlling cardiac myocyte activity with optogenetic tools offer exciting possibilities for fundamental and translational cardiovascular research. Genetically encoded voltage indicators may be particularly attractive for minimal invasive and repeated assessments of cardiac excitation from the cellular to the whole heart level. Objective: To test the hypothesis that cardiac myocyte–targeted voltage-sensitive fluorescence protein 2.3 (VSFP2.3) can be exploited as optogenetic tool for the monitoring of electric activity in isolated cardiac myocytes and the whole heart as well as function and maturity in induced pluripotent stem cell–derived cardiac myocytes. Methods and Results: We first generated mice with cardiac myocyte–restricted expression of VSFP2.3 and demonstrated distinct localization of VSFP2.3 at the t-tubulus/junctional sarcoplasmic reticulum microdomain without any signs for associated pathologies (assessed by echocardiography, RNA-sequencing, and patch clamping). Optically recorded VSFP2.3 signals correlated well with membrane voltage measured simultaneously by patch clamping. The use of VSFP2.3 for human action potential recordings was confirmed by simulation of immature and mature action potentials in murine VSFP2.3 cardiac myocytes. Optical cardiograms could be monitored in whole hearts ex vivo and minimally invasively in vivo via fiber optics at physiological heart rate (10 Hz) and under pacing-induced arrhythmia. Finally, we reprogrammed tail-tip fibroblasts from transgenic mice and used the VSFP2.3 sensor for benchmarking functional and structural maturation in induced pluripotent stem cell–derived cardiac myocytes. Conclusions: We introduce a novel transgenic voltage-sensor model as a new method in cardiovascular research and provide proof of concept for its use in optogenetic sensing of physiological and pathological excitation in mature and immature cardiac myocytes in vitro and in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

Sensing Cardiac Electrical Activity With a Cardiac Myocyte–Targeted Optogenetic Voltage Indicator

Liao

Boer

Mutoh

et al. 2015

Circulation Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Also, there have been some reports in which the pharmacology of standard compounds has proven inconsistent with cardiac cells, raising the question of the reliability of the assay relative to human cardiac tissue. [47][48][49][50] It should be noted that recordings from stem cell-derived myocytes do not fully recapitulate ECG measurements from the intact heart in situ, although they may reveal the propensity of a compound to delay repolarization and favor EAD generation. In addition, CiPA will not address the issue of compounds that prolong the QT interval via changes in autonomic tone or blood pressure.…”

Section: Limitations and Challengesmentioning

confidence: 99%

A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm

et al. 2016

View full text Add to dashboard Cite

For the past decade, cardiac safety screening to evaluate the propensity of drugs to produce QT interval prolongation and Torsades de Pointes (TdP) arrhythmia has been conducted according to ICH S7B and ICH E14 guidelines. Central to the existing approach are hERG channel assays and in vivo QT measurements. Although effective, the present paradigm carries a risk of unnecessary compound attrition and high cost, especially when considering costly thorough QT (TQT) studies conducted later in drug development. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative is a publicprivate collaboration with the aim of updating the existing cardiac safety testing paradigm to better evaluate arrhythmia risk and remove the need for TQT studies. It is hoped that CiPA will produce a standardized ion channel assay approach, incorporating defined tests against major cardiac ion channels, the results of which then inform evaluation of proarrhythmic actions in silico, using human ventricular action potential reconstructions. Results are then to be confirmed using human (stem cell-derived) cardiomyocytes. This perspective article reviews the rationale, progress of, and challenges for the CiPA initiative, if this new paradigm is to replace existing practice and, in time, lead to improved and widely accepted cardiac safety testing guidelines.

show abstract

“…For example, currently available hSCCMs do not exhibit the overall genetic, mechanical, and 3D electrophysiological properties of native, adult human healthy ventricular myocytes. Nevertheless, there is robust experimental evidence that hSC-CMs can correctly identify numerous, albeit not all, proarrhythmic drugs as indicated by published works (Jonsson et al, 2012;Nakamura et al, 2014;Navarrete et al, 2013;Roden and Hong, 2013;Qu and Vargas, in press). Thus, from a functional point of view, the CiPA proarrhythmic assays in hSC-CMs provide, at least in part, the sought information.…”

Section: Discussionmentioning

confidence: 99%

“…These phenotypes may be explained by differences in functional maturation caused by culture conditions. Hence, currently available hSC-CMs neither completely recapitulate the electrophysiological profile of native healthy adult human CMs (the cells considered to be the most appropriate for the third CiPA assay) nor consistently replicate the pharmacological profile (established in native adult CMs) nor differentiate Na + from hhERG channel blockade of certain established proarrhythmic agents (Jonsson et al, 2012;Roden and Hong, 2013;Qu and Vargas, in press). This implies that numerous aspects of hSC-CMs used for the third CiPA assay should be further clarified and appropriately defined in protocols applied to assess the proarrhythmic risks of candidate drugs.…”

Section: Characterization Of Hsc-cm Lines As Biological Materials For mentioning

confidence: 95%

CiPA: Ongoing testing, future qualification procedures, and pending issues

Cavero¹,

Holzgrefe²

2015

Journal of Pharmacological and Toxicological Methods

View full text Add to dashboard Cite

Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG

Cited by 130 publications

References 53 publications

Sensing Cardiac Electrical Activity With a Cardiac Myocyte–Targeted Optogenetic Voltage Indicator

Sensing Cardiac Electrical Activity With a Cardiac Myocyte–Targeted Optogenetic Voltage Indicator

A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm

CiPA: Ongoing testing, future qualification procedures, and pending issues

Contact Info

Product

Resources

About