Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology.
Bottom Line: 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.
Affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands email@example.com firstname.lastname@example.org.Show MeSH
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Mentions: Drugs developed to target Kv1.5 channels would ideally offer atrial selectivity and have no proarrhythmic effect, since IKur conducted by these channels is absent in the ventricles. To determine the response of hESC-atrial CMs to blockers that act on repolarizing potassium currents expressed preferentially in atrial CMs, we tested the effect of a selective Kv1.5 blocker, XEN-D0101 (Ford et al, 2013). Figure8A shows typical APs of hESC-atrial and hESC-ventricular CMs at 1 Hz in the absence and presence of 3 μmol/l XEN-D0101. Treatment with XEN-D0101 caused robust elevation of APAplat (> 26 mV) as well significant prolongation of APD20 (> 30 ms), APD50 (> 35 ms) and APD90 (> 23 ms) in hESC-atrial cells, but the compound did not s ignificantly alter any AP parameter in hESC-ventricular CMs (Fig8A and Supplementary Table S7). AP changes caused by XEN-D0101 were reversible upon washout. The effect of XEN-D0101 on APD20 and APD50 of hESC-atrial CMs is consistent with the effects observed in native human atrial trabeculae in SR (Ford et al, 2013). On the contrary, XEN-D0101 significantly altered APA (> 10 mV) and dV/dtmax (> 8 V/s) in hESC-atrial CMs compared with atrial trabeculae in SR. Intriguingly, XEN-D0101 prolonged APD90 in hESC-atrial CMs as well as in human atrial trabeculae (Ford et al, 2013) in AF while a reduction was observed in SR.
Affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands email@example.com firstname.lastname@example.org.