Human embryonic stem cell derived cardiac myocytes detect hERG-mediated repolarization effects, but not Nav1.5 induced depolarization delay

Qu, Yusheng; Gao, BaoXi; Fang, Mei; Vargas, Hugo M.

doi:10.1016/j.vascn.2013.03.001

Cited by 31 publications

(13 citation statements)

References 37 publications

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“…However, mexiletine induced CE events in 30% of the transients, at the highest concentration tested [30-fold the fETPC; n = 7 cells (1 heart); Figure 5A ]. This observation is consistent with the known sodium channel inhibitory activity of mexiletine (Qu et al, 2013 ). Relaxation time was significantly prolonged only by ranolazine at the highest concentration tested [100-fold of fETPC; 37 ± 11%; n = 3 cells (1 heart); Figure 5B ]; this finding is consistent with the fact that ranolazine is known to induce QT interval prolongation at concentrations above the therapeutic dose (Chaitman, 2004 ; Johannesen et al, 2014 ).…”

Section: Resultssupporting

confidence: 91%

“…While the degree of success of hSC-CMs in correctly classifying pro- and non-proarrhythmic drugs varies, it is also apparent that hSC-CMs have a particularly high rate of false positive and false negative findings when multi-ion channel blockers are tested. This is not surprising, given the known challenges in fully differentiating these cells into a desired cardiac subtype and maturing them to the adult phenotype, which most likely results in non-physiological levels of expression of the conductances that govern the cardiac AP (Qu et al, 2013 ; Blinova et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

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Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug-Induced Inotropic and Pro-arrhythmia Risk

Nguyen

Nguyenton

et al. 2017

Front. Physiol.

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Cardiac safety remains the leading cause of drug development discontinuation. We developed a human cardiomyocyte-based model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic and pro-arrhythmia risk.Methods: Adult human primary cardiomyocytes from ethically consented organ donors were used to measure contractility transients. We used measures of changes in contractility parameters as markers to infer both drug-induced inotropic effect (sarcomere shortening) and pro-arrhythmia (aftercontraction, AC); contractility escape (CE); time to 90% relaxation (TR90). We addressed the clinical relevance of this approach by evaluating the effects of 23 torsadogenic and 10 non-torsadogenic drugs. Each drug was tested separately at four multiples of the free effective therapeutic plasma concentration (fETPC).Results: Human cardiomyocyte-based model differentiated between torsadogenic and non-torsadogenic drugs. For example, dofetilide, a torsadogenic drug, caused ACs and increased TR90 starting at 10-fold the fETPC, while CE events were observed at the highest multiple of fETPC (100-fold). Verapamil, a non-torsadogenic drug, did not change TR90 and induced no AC or CE up to the highest multiple of fETPCs tested in this study (222-fold). When drug pro-arrhythmic activity was evaluated at 10-fold of the fETPC, AC parameter had excellent assay sensitivity and specificity values of 96 and 100%, respectively. This high predictivity supports the translational safety potential of this preparation and of the selected marker. The data demonstrate that human cardiomyocytes could also identify drugs associated with inotropic effects. hERG channel blockers, like dofetilide, had no effects on sarcomere shortening, while multi-ion channel blockers, like verapamil, inhibited sarcomere shortening.Conclusions: Isolated adult human primary cardiomyocytes can simultaneously predict risks associated with inotropic activity and pro-arrhythmia and may enable the generation of reliable and predictive data for assessing human cardiotoxicity at an early stage in drug discovery.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug-Induced Inotropic and Pro-arrhythmia Risk

Nguyen

Nguyenton

et al. 2017

Front. Physiol.

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“…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

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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.

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“…For understanding the potential of hSC-CM in assessing pro-arrhythmic risk, we have tested a set of 15 compounds (ten hERG blockers; four Na channel blockers; one IKs blocker) with a well understood pro-arrhythmic potential in two models of hSC-CM: (1) human embryonic stem cell (hESC)-CM model using traditional patch clamp technique (Qu et al, 2013 ), and (2) human induced pluripotent stem cell (hiPSC)-CM model using Maestro multi-electrode array (MEA) platform (Qu and Vargas, 2015 ). This set includes 6 compounds that are included in the CiPA calibration set: dofetilide, sotalol, cisapride, terfanadine, mexiletine, and ranolazine, with 2 in each TdP risk categories (high, intermediate, and low).…”

Section: Introductionmentioning

confidence: 99%

Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae

Page

Abi‐Gerges

et al. 2018

Front. Physiol.

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To assess drug-induced pro-arrhythmic risk, especially Torsades de Pointe (TdP), new models have been proposed, such as in-silico modeling of ventricular action potential (AP) and stem cell-derived cardiomyocytes (SC-CMs). Previously we evaluated the electrophysiological profile of 15 reference drugs in hESC-CMs and hiPSC-CMs for their effects on intracellular AP and extracellular field potential, respectively. Our findings indicated that SC-CMs exhibited immature phenotype and had the propensity to generate false positives in predicting TdP risk. To expand our knowledge with mature human cardiac tissues for drug-induced pro-arrhythmic risk assessment, human ventricular trabeculae (hVT) from ethically consented organ donors were used to evaluate the effects of the same 15 drugs (8 torsadogenic, 5 non-torsadogenic, and 2 discovery molecules) on AP parameters at 1 and 2 Hz. Each drug was tested blindly with 4 concentrations in duplicate trabeculae from 2 hearts. To identify the pro-arrhythmic risk of each drug, a pro-arrhythmic score was calculated as the weighted sum of percent drug-induced changes compared to baseline in various AP parameters, including AP duration and recognized pro-arrhythmia predictors such as triangulation, beat-to-beat variability and incidence of early-afterdepolarizations, at each concentration. In addition, to understand the translation of this preclinical hVT AP-based model to clinical studies, a ratio that relates each testing concentration to the human therapeutic unbound Cmax (Cmax) was calculated. At a ratio of 10, for the 8 torsadogenic drugs, 7 were correctly identified by the pro-arrhythmic score; 1 was mislabeled. For the 5 non-torsadogenic drugs, 4 were correctly identified as safe; 1 was mislabeled. Calculation of sensitivity, specificity, positive predictive value, and negative predictive value indicated excellent performance. For example, at a ratio of 10, scores for sensitivity, specificity, positive predictive value and negative predictive values were 0.88, 0.8, 0.88 and 0.8, respectively. Thus, the hVT AP-based model combined with the integrated analysis of pro-arrhythmic score can differentiate between torsadogenic and non-torsadogenic drugs, and has a greater predictive performance when compared to human SC-CM models.

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Human embryonic stem cell derived cardiac myocytes detect hERG-mediated repolarization effects, but not Nav1.5 induced depolarization delay

Cited by 31 publications

References 37 publications

Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug-Induced Inotropic and Pro-arrhythmia Risk

Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug-Induced Inotropic and Pro-arrhythmia Risk

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

Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae

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