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Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology.

Devalla HD, Schwach V, Ford JW, Milnes JT, El-Haou S, Jackson C, Gkatzis K, Elliott DA, Chuva de Sousa Lopes SM, Mummery CL, Verkerk AO, Passier R - EMBO Mol Med (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands h.d.devalla@lumc.nl r.passier@lumc.nl.

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Effects of XEN-D0101 and XEN-R0703 on APs of hESC-ventricular and hESC-atrial CMsA Representative APs of VM and AM CMs in the absence, presence and following washout of 3 μmol/l XEN-D0101. AP parameters are shown in Supplementary Table S7.B Representative APs (1 Hz) of VM and AM in the CCh, to activate IK,ACh and subsequent addition of XEN-R0703. AP parameters are shown in Supplementary Table S9.C, D Experiments performed in RAP conscious dogs in the presence of vehicle or following 1, 3 and 10 mg/kg XEN-R0703 show (C) mean right AERP values (left), mean Van de Water's QTc (right) and (D) AF inducibility plotted as a function of dose.Data information: For RAP dog experiments, n = 5; statistical significance tested with paired t-test. Data are presented as mean ± SEM. AERP = atrial effective refractory period; AF = atrial fibrillation; RAP = rapid atrial pacing; N.S. = not significant. Other abbreviations as in Figs3, 6 and 7.
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fig08: Effects of XEN-D0101 and XEN-R0703 on APs of hESC-ventricular and hESC-atrial CMsA Representative APs of VM and AM CMs in the absence, presence and following washout of 3 μmol/l XEN-D0101. AP parameters are shown in Supplementary Table S7.B Representative APs (1 Hz) of VM and AM in the CCh, to activate IK,ACh and subsequent addition of XEN-R0703. AP parameters are shown in Supplementary Table S9.C, D Experiments performed in RAP conscious dogs in the presence of vehicle or following 1, 3 and 10 mg/kg XEN-R0703 show (C) mean right AERP values (left), mean Van de Water's QTc (right) and (D) AF inducibility plotted as a function of dose.Data information: For RAP dog experiments, n = 5; statistical significance tested with paired t-test. Data are presented as mean ± SEM. AERP = atrial effective refractory period; AF = atrial fibrillation; RAP = rapid atrial pacing; N.S. = not significant. Other abbreviations as in Figs3, 6 and 7.

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.


Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology.

Devalla HD, Schwach V, Ford JW, Milnes JT, El-Haou S, Jackson C, Gkatzis K, Elliott DA, Chuva de Sousa Lopes SM, Mummery CL, Verkerk AO, Passier R - EMBO Mol Med (2015)

Effects of XEN-D0101 and XEN-R0703 on APs of hESC-ventricular and hESC-atrial CMsA Representative APs of VM and AM CMs in the absence, presence and following washout of 3 μmol/l XEN-D0101. AP parameters are shown in Supplementary Table S7.B Representative APs (1 Hz) of VM and AM in the CCh, to activate IK,ACh and subsequent addition of XEN-R0703. AP parameters are shown in Supplementary Table S9.C, D Experiments performed in RAP conscious dogs in the presence of vehicle or following 1, 3 and 10 mg/kg XEN-R0703 show (C) mean right AERP values (left), mean Van de Water's QTc (right) and (D) AF inducibility plotted as a function of dose.Data information: For RAP dog experiments, n = 5; statistical significance tested with paired t-test. Data are presented as mean ± SEM. AERP = atrial effective refractory period; AF = atrial fibrillation; RAP = rapid atrial pacing; N.S. = not significant. Other abbreviations as in Figs3, 6 and 7.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4403042&req=5

fig08: Effects of XEN-D0101 and XEN-R0703 on APs of hESC-ventricular and hESC-atrial CMsA Representative APs of VM and AM CMs in the absence, presence and following washout of 3 μmol/l XEN-D0101. AP parameters are shown in Supplementary Table S7.B Representative APs (1 Hz) of VM and AM in the CCh, to activate IK,ACh and subsequent addition of XEN-R0703. AP parameters are shown in Supplementary Table S9.C, D Experiments performed in RAP conscious dogs in the presence of vehicle or following 1, 3 and 10 mg/kg XEN-R0703 show (C) mean right AERP values (left), mean Van de Water's QTc (right) and (D) AF inducibility plotted as a function of dose.Data information: For RAP dog experiments, n = 5; statistical significance tested with paired t-test. Data are presented as mean ± SEM. AERP = atrial effective refractory period; AF = atrial fibrillation; RAP = rapid atrial pacing; N.S. = not significant. Other abbreviations as in Figs3, 6 and 7.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands h.d.devalla@lumc.nl r.passier@lumc.nl.

Show MeSH
Related in: MedlinePlus