Open AccessModeling Short QT Syndrome Using Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes
Author(s) -
ElBattrawy Ibrahim,
Lan Huan,
Cyganek Lukas,
Zhao Zhihan,
Li Xin,
Buljubasic Fanis,
Lang Siegfried,
Yücel Gökhan,
Sattler Katherine,
Zimmermann WolframHubertus,
Utikal Jochen,
Wieland Thomas,
Ravens Ursula,
Borggrefe Martin,
Zhou XiaoBo,
Akin Ibrahim
Publication year - 2018
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.007394
Subject(s) - short qt syndrome , induced pluripotent stem cell , herg , medicine , long qt syndrome , qt interval , cardiology , potassium channel , biology , genetics , gene , embryonic stem cell
Background Short QT syndrome ( SQTS ), a disorder associated with characteristic ECG QT ‐segment abbreviation, predisposes affected patients to sudden cardiac death. Despite some progress in assessing the organ‐level pathophysiology and genetic changes of the disorder, the understanding of the human cellular phenotype and discovering of an optimal therapy has lagged because of a lack of appropriate human cellular models of the disorder. The objective of this study was to establish a cellular model of SQTS using human‐induced pluripotent stem cell–derived cardiomyocytes (hi PSC ‐ CM s). Methods and Results This study recruited 1 patient with short QT syndrome type 1 carrying a mutation (N588K) in KCNH 2 as well as 2 healthy control subjects. We generated hi PSC s from their skin fibroblasts, and differentiated hi PSC s into cardiomyocytes (hi PSC ‐ CM s) for physiological and pharmacological studies. The hi PSC ‐ CM s from the patient showed increased rapidly activating delayed rectifier potassium channel current ( I K r ) density and shortened action potential duration compared with healthy control hi PSC ‐ CM s. Furthermore, they demonstrated abnormal calcium transients and rhythmic activities. Carbachol increased the arrhythmic events in SQTS but not in control cells. Gene and protein expression profiling showed increased KCNH 2 expression in SQTS cells. Quinidine but not sotalol or metoprolol prolonged the action potential duration and abolished arrhythmic activity induced by carbachol. Conclusions Patient‐specific hi PSC ‐ CM s are able to recapitulate single‐cell phenotype features of SQTS and provide novel opportunities to further elucidate the cellular disease mechanism and test drug effects.