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

Abstract

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.

An in Vitro Assay of hERG K+ Channel Potency for a New EGFR Inhibitor FHND004

“…On the other hand, drug-induced proarrhythmia can occur in the absence of hERG inhibition via direct inhibition of other repolarizing ion channels ( Lane and Tinker, 2017 ). Therefore, it is worthwhile to further examine the effects of FHND004 on cardiomyocytes derived from human induced pluripotent stem cell (iPSC; Takasuna et al, 2017 ), or mature human ventricular tissue ( Qu et al, 2017 ).…”

Cardiotoxic Potential of Hydroxychloroquine, Chloroquine and Azithromycin in Adult Human Primary Cardiomyocytes

“…Challenges in translating preclinical cardiac safety data to humans has accelerated the search for developing novel human-relevant platforms to bridge translational gaps ( Abi-Gerges et al , 2020a ; Pang et al , 2019 ). Predictive adult human cardiac tissue- and cardiomyocyte-based models from healthy organ donors are now available for preclinical discovery studies ( Abi-Gerges et al , 2020b ; Britton et al , 2017 ; Nguyen et al , 2017 ; Otsomaa et al , 2020 ; Page et al , 2016 ; Qu et al , 2018 ; Trovato et al , 2020 ). The cardiomyocyte contractility-based model has been shown to simultaneously predict drug-induced inotropic and proarrhythmia risk ( Nguyen et al , 2017 ), and provide multiparametric mechanistic profiling of drugs ( Abi-Gerges et al , 2020b ).…”

The Potential Role of the J‐Tpeak Interval in Proarrhythmic Cardiac Safety: Current State of the Science From the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium

“…With regard to drug-induced torsade, the 2 most important currents in addition to hERG are inward depolarizing currents: the late sodium current and the L-type calcium current (see also Figure 1). Blocking of these currents in animals, 6,7 human cells, 8 and in in-silico models 9 shortens the action potential duration of cardiac cells in the ventricle and prevents the occurrence of early afterdepolarizations, which are the trigger of torsade. 10,11 Moreover, mexiletine (late sodium block) mitigated recurrent torsade caused by acquired long-QT syndrome in a recent clinical study.…”