Affiliation:
1. Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (M.K., D.Y., C.S.J.K., W.Z., D.J.T., J.R.G., M.J.A.).
2. Departments of Cardiovascular Medicine (Clinician-Investigator Training Program), Mayo Clinic, Rochester, MN (J.R.G.).
Abstract
Background:
Prior epidemiological studies demonstrated that the p.D85N-Potassium voltage-gated channel subfamily E member 1 (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 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 heart rate-corrected QT interval response to metoclopramide (ΔQTc of 160 ms). Clustered regularly interspaced short palindromic repeats-associated 9 technology was used to generate gene-corrected isogenic iPSCs. Field potential duration and action potential duration (APD) were measured from iPSC-CMs.
Results:
At baseline, p.D85N-KCNE1 iPSC-CMs displayed significantly longer field potential duration (281±15 ms, n=13 versus 223±8.6 ms, n=14,
P
<0.01) and action potential duration at 90% repolarization (APD90; 579±22 ms, n=24 versus 465±33 ms, n=26,
P
<0.01) than isogenic-control iPSC-CMs. Dofetilide at a concentration of 2 nM increased significantly field potential duration (379±20 ms, n=13,
P
<0.01) and APD90 (666±11 ms, n=46,
P
<0.01) in p.D85N-KCNE1 iPSC-CMs but not in isogenic-control. The effect of dofetilide on APD90 (616±54 ms, n=7 versus 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 1 nM exaggerated further dofetilide-induced APD90 prolongation (696±9 ms, n=81,
P
<0.01) and caused more early afterdepolarizations (11.7%) compared with isogenic control (APD90: 618±8 ms, n=115 and early afterdepolarizations: 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 proarrhythmic.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Cited by
7 articles.
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