Abstract:
:Current cardiac drug safety assessments focus on hERG channel block and QT prolongation for evaluating arrhythmic risks, whereas the optogenetic approach focuses on the action potential (AP) waveform generated by a monolayer of human cardiomyocytes beating synchronously, thus assessing the contribution of several ion channels on the overall drug effect. This novel tool provides arrhythmogenic sensitizing by light-induced pacing in combination with non-invasive, all-optical measurements of cardiomyocyte APs and will improve assessment of drug-induced electrophysiological aberrancies. With the help of patch clamp electrophysiology measurements, we aimed to investigate whether the optogenetic modifications alter human cardiomyocytes' electrophysiology and how well the optogenetic analyses perform against this gold standard. Patch clamp electrophysiology measurements of non-transduced stem cell-derived cardiomyocytes compared to cells expressing the commercially available optogenetic constructs Optopatch and CaViar revealed no significant changes in action potential duration (APD) parameters. Thus, inserting the optogenetic constructs into cardiomyocytes does not significantly affect the cardiomyocyte's electrophysiological properties. When comparing the two methods against each other (patch clamp vs. optogenetic imaging) we found no significant differences in APD parameters for the Optopatch transduced cells, whereas the CaViar transduced cells exhibited modest increases in APD-values measured with optogenetic imaging. Thus, to broaden the screen, we combined optogenetic measurements of membrane potential and calcium transients with contractile motion measured by video motion tracking. Furthermore, to assess how optogenetic measurements can predict changes in membrane potential, or early afterdepolarizations (EADs), cells were exposed to cumulating doses of E-4031, a hERG potassium channel blocker, and drug effects were measured at both spontaneous and paced beating rates (1, 2 Hz). Cumulating doses of E-4031 produced prolonged APDs, followed by EADs and drug-induced quiescence. These observations were corroborated by patch clamp and contractility measurements. Similar responses, although more modest were seen with the IKs potassium channel blocker JNJ-303. In conclusion, optogenetic measurements of AP waveforms combined with optical pacing compare well with the patch clamp gold standard. Combined with video motion contractile measurements, optogenetic imaging provides an appealing alternative for electrophysiological screening of human cardiomyocyte responses in pharmacological efficacy and safety testings.
journal_name
Front Physioljournal_title
Frontiers in physiologyauthors
Björk S,Ojala EA,Nordström T,Ahola A,Liljeström M,Hyttinen J,Kankuri E,Mervaala Edoi
10.3389/fphys.2017.00884subject
Has Abstractpub_date
2017-11-02 00:00:00pages
884issn
1664-042Xjournal_volume
8pub_type
杂志文章abstract:PURPOSE:While the intention of endurance athletes undertaking short term heat training protocols is to rapidly gain meaningful physical adaption prior to competition in the heat, it is currently unclear whether or not this process also presents an overt, acute challenge to the immune system. The aim of this study was t...
journal_title:Frontiers in physiology
pub_type: 杂志文章
doi:10.3389/fphys.2016.00318
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pub_type: 杂志文章,评审
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journal_title:Frontiers in physiology
pub_type: 杂志文章,评审
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journal_title:Frontiers in physiology
pub_type: 杂志文章
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pub_type: 杂志文章,评审
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pub_type: 杂志文章,评审
doi:10.3389/fphys.2018.01487
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journal_title:Frontiers in physiology
pub_type: 杂志文章
doi:10.3389/fphys.2014.00431
更新日期:2014-11-12 00:00:00
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journal_title:Frontiers in physiology
pub_type: 杂志文章
doi:10.3389/fphys.2018.00491
更新日期:2018-05-04 00:00:00
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journal_title:Frontiers in physiology
pub_type: 杂志文章
doi:10.3389/fphys.2019.00373
更新日期:2019-04-04 00:00:00
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journal_title:Frontiers in physiology
pub_type: 杂志文章
doi:10.3389/fphys.2012.00418
更新日期:2012-11-21 00:00:00
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journal_title:Frontiers in physiology
pub_type: 杂志文章
doi:10.3389/fphys.2019.00928
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pub_type: 杂志文章
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journal_title:Frontiers in physiology
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journal_title:Frontiers in physiology
pub_type: 杂志文章,评审
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更新日期:2020-10-30 00:00:00
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journal_title:Frontiers in physiology
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更新日期:2020-08-14 00:00:00
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journal_title:Frontiers in physiology
pub_type: 杂志文章
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更新日期:2013-03-25 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2018-12-18 00:00:00