PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model
BackgroundThe phosphoinositide 3-kinase (PI3K) signaling pathway is an interesting target in cancer treatment. The awareness of the proarrhythmic risk of PI3K inhibitors was raised because PI3K is also involved in regulating signaling toward cardiac ion channels. Canine cardiomyocytes treated with P...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2022.956538/full |
| _version_ | 1811343430027051008 |
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| author | J. J. A. van Bavel C. Pham H. D. M. Beekman M. J. C. Houtman A. Bossu R. W. Sparidans M. A. G. van der Heyden M. A. Vos |
| author_facet | J. J. A. van Bavel C. Pham H. D. M. Beekman M. J. C. Houtman A. Bossu R. W. Sparidans M. A. G. van der Heyden M. A. Vos |
| author_sort | J. J. A. van Bavel |
| collection | DOAJ |
| description | BackgroundThe phosphoinositide 3-kinase (PI3K) signaling pathway is an interesting target in cancer treatment. The awareness of the proarrhythmic risk of PI3K inhibitors was raised because PI3K is also involved in regulating signaling toward cardiac ion channels. Canine cardiomyocytes treated with PI3K inhibitors show an increased action potential duration and reduced cardiac repolarizing currents. Now, the potential proarrhythmic effect of chronic treatment of PI3K/mTOR inhibitor GSK2126458 (omipalisib) was investigated in the atrioventricular (AV) block dog model.MethodsPurpose-bred Mongrel dogs received complete AV block by ablation of the bundle of His and their hearts were paced in the right ventricular apex at VDD-mode (RVA-VDD). In this way, sinus rhythm was maintained for 15 ± 1 days and thereby bradycardia-induced cardiac remodeling was prevented. Dogs received 1 mg/kg omipalisib once (n = 3) or twice (n = 10) a day via oral administration for 7 days. Under standardized conditions (anesthesia, bradycardia at 60 beats/min, and a dofetilide challenge), potential proarrhythmic effects of omipalisib were investigated.ResultsTwice daily dosing of omipalisib increased accumulative plasma levels compared to once daily dosing accompanied with adverse events. Omipalisib prolonged the QT interval at baseline and more strongly after the dofetilide challenge (490 ± 37 to 607 ± 48 ms). The arrhythmic outcome after omipalisib resulted in single ectopic beats in 30% of dogs perpetuating in multiple ectopic beats and TdP arrhythmia in 20% of dogs. Isolated ventricular cardiomyocytes from omipalisib-treated dogs showed a diminished IKs current density.ConclusionChronic treatment of PI3K/mTOR inhibitor omipalisib prolonged the QT interval in a preclinical model under standardized proarrhythmic conditions. Furthermore, this study showed that electrical remodeling induced by omipalisib had a mild proarrhythmic outcome. |
| first_indexed | 2024-04-13T19:29:18Z |
| format | Article |
| id | doaj.art-babebe5088204972a6e5d4822409d2e5 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-13T19:29:18Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-babebe5088204972a6e5d4822409d2e52022-12-22T02:33:15ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2022-08-01910.3389/fcvm.2022.956538956538PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog modelJ. J. A. van Bavel0C. Pham1H. D. M. Beekman2M. J. C. Houtman3A. Bossu4R. W. Sparidans5M. A. G. van der Heyden6M. A. Vos7Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, NetherlandsDivision of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, NetherlandsDivision of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, NetherlandsDivision of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, NetherlandsDivision of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, NetherlandsDivision Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, NetherlandsDivision of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, NetherlandsDivision of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, NetherlandsBackgroundThe phosphoinositide 3-kinase (PI3K) signaling pathway is an interesting target in cancer treatment. The awareness of the proarrhythmic risk of PI3K inhibitors was raised because PI3K is also involved in regulating signaling toward cardiac ion channels. Canine cardiomyocytes treated with PI3K inhibitors show an increased action potential duration and reduced cardiac repolarizing currents. Now, the potential proarrhythmic effect of chronic treatment of PI3K/mTOR inhibitor GSK2126458 (omipalisib) was investigated in the atrioventricular (AV) block dog model.MethodsPurpose-bred Mongrel dogs received complete AV block by ablation of the bundle of His and their hearts were paced in the right ventricular apex at VDD-mode (RVA-VDD). In this way, sinus rhythm was maintained for 15 ± 1 days and thereby bradycardia-induced cardiac remodeling was prevented. Dogs received 1 mg/kg omipalisib once (n = 3) or twice (n = 10) a day via oral administration for 7 days. Under standardized conditions (anesthesia, bradycardia at 60 beats/min, and a dofetilide challenge), potential proarrhythmic effects of omipalisib were investigated.ResultsTwice daily dosing of omipalisib increased accumulative plasma levels compared to once daily dosing accompanied with adverse events. Omipalisib prolonged the QT interval at baseline and more strongly after the dofetilide challenge (490 ± 37 to 607 ± 48 ms). The arrhythmic outcome after omipalisib resulted in single ectopic beats in 30% of dogs perpetuating in multiple ectopic beats and TdP arrhythmia in 20% of dogs. Isolated ventricular cardiomyocytes from omipalisib-treated dogs showed a diminished IKs current density.ConclusionChronic treatment of PI3K/mTOR inhibitor omipalisib prolonged the QT interval in a preclinical model under standardized proarrhythmic conditions. Furthermore, this study showed that electrical remodeling induced by omipalisib had a mild proarrhythmic outcome.https://www.frontiersin.org/articles/10.3389/fcvm.2022.956538/fullomipalisibAV block dog modelQT prolongationPI3K inhibitionventricular arrhythmia (VA) |
| spellingShingle | J. J. A. van Bavel C. Pham H. D. M. Beekman M. J. C. Houtman A. Bossu R. W. Sparidans M. A. G. van der Heyden M. A. Vos PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model Frontiers in Cardiovascular Medicine omipalisib AV block dog model QT prolongation PI3K inhibition ventricular arrhythmia (VA) |
| title | PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model |
| title_full | PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model |
| title_fullStr | PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model |
| title_full_unstemmed | PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model |
| title_short | PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model |
| title_sort | pi3k mtor inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the av block dog model |
| topic | omipalisib AV block dog model QT prolongation PI3K inhibition ventricular arrhythmia (VA) |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2022.956538/full |
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