Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae
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 drug...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-01-01
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| Series: | Frontiers in Physiology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphys.2017.01109/full |
| _version_ | 1819149616206053376 |
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| author | Yusheng Qu Guy Page Najah Abi-Gerges Paul E. Miller Andre Ghetti Hugo M. Vargas |
| author_facet | Yusheng Qu Guy Page Najah Abi-Gerges Paul E. Miller Andre Ghetti Hugo M. Vargas |
| author_sort | Yusheng Qu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T14:04:26Z |
| format | Article |
| id | doaj.art-ec8a7ab55f82419091b2e536c293fa1a |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-22T14:04:26Z |
| publishDate | 2018-01-01 |
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| series | Frontiers in Physiology |
| spelling | doaj.art-ec8a7ab55f82419091b2e536c293fa1a2022-12-21T18:23:20ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2018-01-01810.3389/fphys.2017.01109307780Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular TrabeculaeYusheng Qu0Guy Page1Najah Abi-Gerges2Paul E. Miller3Andre Ghetti4Hugo M. Vargas5Integrated Discovery and Safety Pharmacology, Amgen Inc., Thousand Oaks, CA, United StatesAnaBios Corporation, San Diego, CA, United StatesAnaBios Corporation, San Diego, CA, United StatesAnaBios Corporation, San Diego, CA, United StatesAnaBios Corporation, San Diego, CA, United StatesIntegrated Discovery and Safety Pharmacology, Amgen Inc., Thousand Oaks, CA, United StatesTo 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.http://journal.frontiersin.org/article/10.3389/fphys.2017.01109/fullaction potentialPro-arrhythmic riskhuman ventricular tissueTdP assessementIn-vitro models |
| spellingShingle | Yusheng Qu Guy Page Najah Abi-Gerges Paul E. Miller Andre Ghetti Hugo M. Vargas Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae Frontiers in Physiology action potential Pro-arrhythmic risk human ventricular tissue TdP assessement In-vitro models |
| title | Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae |
| title_full | Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae |
| title_fullStr | Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae |
| title_full_unstemmed | Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae |
| title_short | Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae |
| title_sort | action potential recording and pro arrhythmia risk analysis in human ventricular trabeculae |
| topic | action potential Pro-arrhythmic risk human ventricular tissue TdP assessement In-vitro models |
| url | http://journal.frontiersin.org/article/10.3389/fphys.2017.01109/full |
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