Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart
Abstract Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in a...
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2021
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oai:doaj.org-article:9370b3fc5ae4452d944997c5ebf6e2622021-12-02T17:52:13ZArrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart10.1038/s41598-021-91528-12045-2322https://doaj.org/article/9370b3fc5ae4452d944997c5ebf6e2622021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91528-1https://doaj.org/toc/2045-2322Abstract Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca2+ homeostasis, increased contractility, and increased the manifestation of arrhythmia markers. These effects could be reversed by late INa inhibitors, ranolazine and GS-967. We also report that atrial tissues from donor hearts affected by atrial fibrillation exhibit arrhythmia markers in the absence of drug treatment and inhibition of late INa with GS-967 leads to a significant reduction in arrhythmic behaviour. These findings reveal a critical role for the late INa in cardiac arrhythmias and suggest that inhibition of this conductance could provide an effective therapeutic strategy. Finally, this study highlights the utility of human ex-vivo heart models for advancing cardiac translational sciences.Anh Tuan TonWilliam NguyenKatrina SweatYannick MironEduardo HernandezTiara WongValentyna GeftAndrew MaciasAna EspinozaKy TruongLana RasoulAlexa StaffordTamara CottaChristina MaiTim IndersmittenGuy PagePaul E. MillerAndre GhettiNajah Abi-GergesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021) |
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Medicine R Science Q |
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Medicine R Science Q Anh Tuan Ton William Nguyen Katrina Sweat Yannick Miron Eduardo Hernandez Tiara Wong Valentyna Geft Andrew Macias Ana Espinoza Ky Truong Lana Rasoul Alexa Stafford Tamara Cotta Christina Mai Tim Indersmitten Guy Page Paul E. Miller Andre Ghetti Najah Abi-Gerges Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart |
| description |
Abstract Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca2+ homeostasis, increased contractility, and increased the manifestation of arrhythmia markers. These effects could be reversed by late INa inhibitors, ranolazine and GS-967. We also report that atrial tissues from donor hearts affected by atrial fibrillation exhibit arrhythmia markers in the absence of drug treatment and inhibition of late INa with GS-967 leads to a significant reduction in arrhythmic behaviour. These findings reveal a critical role for the late INa in cardiac arrhythmias and suggest that inhibition of this conductance could provide an effective therapeutic strategy. Finally, this study highlights the utility of human ex-vivo heart models for advancing cardiac translational sciences. |
| format |
article |
| author |
Anh Tuan Ton William Nguyen Katrina Sweat Yannick Miron Eduardo Hernandez Tiara Wong Valentyna Geft Andrew Macias Ana Espinoza Ky Truong Lana Rasoul Alexa Stafford Tamara Cotta Christina Mai Tim Indersmitten Guy Page Paul E. Miller Andre Ghetti Najah Abi-Gerges |
| author_facet |
Anh Tuan Ton William Nguyen Katrina Sweat Yannick Miron Eduardo Hernandez Tiara Wong Valentyna Geft Andrew Macias Ana Espinoza Ky Truong Lana Rasoul Alexa Stafford Tamara Cotta Christina Mai Tim Indersmitten Guy Page Paul E. Miller Andre Ghetti Najah Abi-Gerges |
| author_sort |
Anh Tuan Ton |
| title |
Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart |
| title_short |
Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart |
| title_full |
Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart |
| title_fullStr |
Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart |
| title_full_unstemmed |
Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart |
| title_sort |
arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/9370b3fc5ae4452d944997c5ebf6e262 |
| work_keys_str_mv |
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