title: Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology.
abstract: Drugs targeting atrial-specific ion channels, Kv1.5 or Kir3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non-cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte (CM). In the current study, we tested whether human embryonic stem cell (hESC)-derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial-like (hESC-atrial) and ventricular-like (hESC-ventricular) CMs. We found the expression of atrial-specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding Kir 3.1), in hESC-atrial CMs and further demonstrated that these ion channel genes are regulated by COUP-TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and Kv1.5 blocker, XEN-D0101, hESC-atrial but not hESC-ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC-atrial CMs, XEN-R0703, a novel Kir3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN-R0703 had an effect on hESC-ventricular CMs. In summary, we demonstrate that hESC-atrial CMs are a robust model for pre-clinical testing to assess atrial selectivity of novel antiarrhythmic drugs.
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands h.d.devalla@lumc.nl r.passier@lumc.nl.
authors.forename: Harsha D
authors.initials: HD
authors.lastname: Devalla
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Verena
authors.initials: V
authors.lastname: Schwach
authors.affiliation: Xention Ltd, Cambridge, UK.
authors.forename: John W
authors.initials: JW
authors.lastname: Ford
authors.affiliation: Xention Ltd, Cambridge, UK.
authors.forename: James T
authors.initials: JT
authors.lastname: Milnes
authors.affiliation: Xention Ltd, Cambridge, UK.
authors.forename: Said
authors.initials: S
authors.lastname: El-Haou
authors.affiliation: Xention Ltd, Cambridge, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Jackson
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Gkatzis
authors.affiliation: Murdoch Childrens Research Institute Royal Children's Hospital, Melbourne, Vic., Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Elliott
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands Department for Reproductive Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Susana M
authors.initials: SM
authors.lastname: Chuva de Sousa Lopes
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
authors.affiliation: Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands h.d.devalla@lumc.nl r.passier@lumc.nl.
authors.forename: Robert
authors.initials: R
authors.lastname: Passier
mesh_terms: D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015870:Gene Expression; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology*
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C496981:KCNA5 protein, human; C497066:KCNJ3 protein, human; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers
keywords: COUP‐TF; arrhythmias; atrial cardiomyocytes; atrial fibrillation; ion channels