Cargando…

Ajmaline blocks I(Na) and I(Kr) without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters

The class Ia anti-arrhythmic drug ajmaline is used clinically to unmask latent type I ECG in Brugada syndrome (BrS) patients, although its mode of action is poorly characterised. Our aims were to identify ajmaline's mode of action in human induced pluripotent stem cell (hiPSC)-derived cardiomyo...

Descripción completa

Detalles Bibliográficos
Autores principales: Miller, Duncan C., Harmer, Stephen C., Poliandri, Ariel, Nobles, Muriel, Edwards, Elizabeth C., Ware, James S., Sharp, Tyson V., McKay, Tristan R., Dunkel, Leo, Lambiase, Pier D., Tinker, Andrew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727153/
https://www.ncbi.nlm.nih.gov/pubmed/29172153
http://dx.doi.org/10.1016/j.scr.2017.11.003
_version_ 1783285817412681728
author Miller, Duncan C.
Harmer, Stephen C.
Poliandri, Ariel
Nobles, Muriel
Edwards, Elizabeth C.
Ware, James S.
Sharp, Tyson V.
McKay, Tristan R.
Dunkel, Leo
Lambiase, Pier D.
Tinker, Andrew
author_facet Miller, Duncan C.
Harmer, Stephen C.
Poliandri, Ariel
Nobles, Muriel
Edwards, Elizabeth C.
Ware, James S.
Sharp, Tyson V.
McKay, Tristan R.
Dunkel, Leo
Lambiase, Pier D.
Tinker, Andrew
author_sort Miller, Duncan C.
collection PubMed
description The class Ia anti-arrhythmic drug ajmaline is used clinically to unmask latent type I ECG in Brugada syndrome (BrS) patients, although its mode of action is poorly characterised. Our aims were to identify ajmaline's mode of action in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), and establish a simple BrS hiPSC platform to test whether differences in ajmaline response could be determined between BrS patients and controls. Control hiPSCs were differentiated into spontaneously contracting cardiac clusters. It was found using multi electrode array (MEA) that ajmaline treatment significantly lengthened cluster activation-recovery interval. Patch clamping of single CMs isolated from clusters revealed that ajmaline can block both I(Na) and I(Kr). Following generation of hiPSC lines from BrS patients (absent of pathogenic SCN5A sodium channel mutations), analysis of hiPSC-CMs from patients and controls revealed that differentiation and action potential parameters were similar. Comparison of cardiac clusters by MEA showed that ajmaline lengthened activation-recovery interval consistently across all lines. We conclude that ajmaline can block both depolarisation and repolarisation of hiPSC-CMs at the cellular level, but that a more refined integrated tissue model may be necessary to elicit differences in its effect between BrS patients and controls.
format Online
Article
Text
id pubmed-5727153
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-57271532017-12-22 Ajmaline blocks I(Na) and I(Kr) without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters Miller, Duncan C. Harmer, Stephen C. Poliandri, Ariel Nobles, Muriel Edwards, Elizabeth C. Ware, James S. Sharp, Tyson V. McKay, Tristan R. Dunkel, Leo Lambiase, Pier D. Tinker, Andrew Stem Cell Res Article The class Ia anti-arrhythmic drug ajmaline is used clinically to unmask latent type I ECG in Brugada syndrome (BrS) patients, although its mode of action is poorly characterised. Our aims were to identify ajmaline's mode of action in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), and establish a simple BrS hiPSC platform to test whether differences in ajmaline response could be determined between BrS patients and controls. Control hiPSCs were differentiated into spontaneously contracting cardiac clusters. It was found using multi electrode array (MEA) that ajmaline treatment significantly lengthened cluster activation-recovery interval. Patch clamping of single CMs isolated from clusters revealed that ajmaline can block both I(Na) and I(Kr). Following generation of hiPSC lines from BrS patients (absent of pathogenic SCN5A sodium channel mutations), analysis of hiPSC-CMs from patients and controls revealed that differentiation and action potential parameters were similar. Comparison of cardiac clusters by MEA showed that ajmaline lengthened activation-recovery interval consistently across all lines. We conclude that ajmaline can block both depolarisation and repolarisation of hiPSC-CMs at the cellular level, but that a more refined integrated tissue model may be necessary to elicit differences in its effect between BrS patients and controls. Elsevier 2017-12 /pmc/articles/PMC5727153/ /pubmed/29172153 http://dx.doi.org/10.1016/j.scr.2017.11.003 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Miller, Duncan C.
Harmer, Stephen C.
Poliandri, Ariel
Nobles, Muriel
Edwards, Elizabeth C.
Ware, James S.
Sharp, Tyson V.
McKay, Tristan R.
Dunkel, Leo
Lambiase, Pier D.
Tinker, Andrew
Ajmaline blocks I(Na) and I(Kr) without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters
title Ajmaline blocks I(Na) and I(Kr) without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters
title_full Ajmaline blocks I(Na) and I(Kr) without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters
title_fullStr Ajmaline blocks I(Na) and I(Kr) without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters
title_full_unstemmed Ajmaline blocks I(Na) and I(Kr) without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters
title_short Ajmaline blocks I(Na) and I(Kr) without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters
title_sort ajmaline blocks i(na) and i(kr) without eliciting differences between brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727153/
https://www.ncbi.nlm.nih.gov/pubmed/29172153
http://dx.doi.org/10.1016/j.scr.2017.11.003
work_keys_str_mv AT millerduncanc ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters
AT harmerstephenc ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters
AT poliandriariel ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters
AT noblesmuriel ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters
AT edwardselizabethc ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters
AT warejamess ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters
AT sharptysonv ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters
AT mckaytristanr ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters
AT dunkelleo ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters
AT lambiasepierd ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters
AT tinkerandrew ajmalineblocksinaandikrwithoutelicitingdifferencesbetweenbrugadasyndromepatientandcontrolhumanpluripotentstemcellderivedcardiacclusters