Studying KCNQ1 Mutation and Drug Response in Type 1 Long QT Syndrome Using Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes

2017 ◽  
pp. 7-28 ◽  
Author(s):  
Heming Wei ◽  
Jianjun Wu ◽  
Zhenfeng Liu
Keyword(s):  
Stem Cell ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cell ◽  
Drug Response ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Long Qt ◽  
Qt Syndrome ◽  
Induced Pluripotent

scholarly journals Elucidating arrhythmogenic mechanisms of long-QT syndrome CALM1-F142L mutation in patient-specific induced pluripotent stem cell-derived cardiomyocytes

2017 ◽  
Vol 113 (5) ◽  
pp. 531-541 ◽  
Author(s):  
Marcella Rocchetti ◽  
Luca Sala ◽  
Lisa Dreizehnter ◽  
Lia Crotti ◽  
Daniel Sinnecker ◽  
...  
Keyword(s):  
Stem Cell ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Long Qt ◽  
Qt Syndrome ◽  
Induced Pluripotent

scholarly journals Patient-Specific Induced Pluripotent Stem-Cell Models for Long-QT Syndrome

2010 ◽  
Vol 363 (15) ◽  
pp. 1397-1409 ◽  
Author(s):  
Alessandra Moretti ◽  
Milena Bellin ◽  
Andrea Welling ◽  
Christian Billy Jung ◽  
Jason T. Lam ◽  
...  
Keyword(s):  
Stem Cell ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Cell Models ◽  
Long Qt ◽  
Qt Syndrome ◽  
Induced Pluripotent ◽  
Stem Cell Models

Development of a Patient-Specific p.D85N-KCNE1 Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for Drug-Induced Long QT Syndrome

2021 ◽  
Author(s):  
Maengjo Kim ◽  
Dan Ye ◽  
CS John Kim ◽  
Wei Zhou ◽  
David J. Tester ◽  
...  
Keyword(s):  
Stem Cell ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Common Variant ◽  
Patient Specific ◽  
Long Qt ◽  
Drug Induced ◽  
Qt Syndrome ◽  
Induced Pluripotent

Background - Prior epidemiological studies demonstrated that the p.D85N-KCNE1 common variant reduces repolarization reserve and predisposes to drug-induced QT prolongation/torsades de pointes. We sought to develop a cellular model for drug-induced long QT syndrome (DI-LQTS) using a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM). Methods - p.D85N-KCNE1 iPSCs were generated from a 23-year-old female with an exaggerated QTc response to metoclopramide (ΔQTc of 160 ms). CRISPR/Cas9 technology was used to generate "gene-corrected" isogenic iPSCs. Field potential duration (FPD) and action potential duration (APD) were measured from iPSC-CMs. Results - At baseline, p.D85N-KCNE1 iPSC-CMs displayed significantly longer FPD (281 ± 15 ms, n=13 vs. 223 ± 8.6 ms, n=14, p<0.01) and APD 90 (579 ± 22 ms, n=24 vs. 465 ± 33 ms, n=26, p<0.01) than isogenic-control iPSC-CMs. Dofetilide at a concentration of 2nM increased significantly FPD (379 ± 20 ms, n=13, p<0.01) and APD 90 (666 ± 11 ms, n=46, p<0.01) in p.D85N-KCNE1 iPSC-CMs, but not in isogenic-control. The effect of dofetilide on APD 90 (616 ± 54 ms, n=7 vs. 526 ± 54 ms, n=10, p<0.05) was confirmed by Patch-clamp. Interestingly, treatment of p.D85N-KCNE1 iPSC-CMs with estrogen at a concentration of 1nM exaggerated further dofetilide-induced APD 90 prolongation (696 ± 9 ms, n=81, p<0.01) and caused more early afterdepolarizations (EADs) (11.7%) compared to isogenic control (APD 90 : 618 ± 8 ms, n=115 and EADs: 2.6%, p<0.05) Conclusions - This iPSC-CM study provides further evidence that the p.D85N-KCNE1 common variant in combination with environmental factors such as QT prolonging drugs and female sex is pro-arrhythmic.

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