title: Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture.
abstract: Long QT syndrome (LQTS) is caused by functional alterations in cardiac ion channels and is associated with prolonged cardiac repolarization time and increased risk of ventricular arrhythmias. Inherited type 2 LQTS (LQT2) and drug-induced LQTS both result from altered function of the hERG channel. We investigated whether the electrophysiological characteristics of LQT2 can be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology. Spontaneously beating cardiomyocytes were differentiated from two iPSC lines derived from an individual with LQT2 carrying the R176W mutation in the KCNH2 (HERG) gene. The individual had been asymptomatic except for occasional palpitations, but his sister and father had died suddenly at an early age. Electrophysiological properties of LQT2-specific cardiomyocytes were studied using microelectrode array and patch-clamp, and were compared with those of cardiomyocytes derived from control cells. The action potential duration of LQT2-specific cardiomyocytes was significantly longer than that of control cardiomyocytes, and the rapid delayed potassium channel (I(Kr)) density of the LQT2 cardiomyocytes was significantly reduced. Additionally, LQT2-derived cardiac cells were more sensitive than controls to potentially arrhythmogenic drugs, including sotalol, and demonstrated arrhythmogenic electrical activity. Consistent with clinical observations, the LQT2 cardiomyocytes demonstrated a more pronounced inverse correlation between the beating rate and repolarization time compared with control cells. Prolonged action potential is present in LQT2-specific cardiomyocytes derived from a mutation carrier and arrhythmias can be triggered by a commonly used drug. Thus, the iPSC-derived, disease-specific cardiomyocytes could serve as an important platform to study pathophysiological mechanisms and drug sensitivity in LQT2.
authors: Institute of Biomedical Technology, University of Tampere, Tampere, Finland.
authors: Anna L
authors: AL
authors: Lahti
authors: Ville J
authors: VJ
authors: Kujala
authors: Hugh
authors: H
authors: Chapman
authors: Ari-Pekka
authors: AP
authors: Koivisto
authors: Mari
authors: M
authors: Pekkanen-Mattila
authors: Erja
authors: E
authors: Kerkelä
authors: Jari
authors: J
authors: Hyttinen
authors: Kimmo
authors: K
authors: Kontula
authors: Heikki
authors: H
authors: Swan
authors: Bruce R
authors: BR
authors: Conklin
authors: Shinya
authors: S
authors: Yamanaka
authors: Olli
authors: O
authors: Silvennoinen
authors: Katriina
authors: K
authors: Aalto-Setälä
mesh_terms: D000200:Action Potentials; D019943:Amino Acid Substitution; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D000072237:ERG1 Potassium Channel; D055724:Electrophysiological Phenomena; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology / Q000502:physiology*; D008133:Long QT Syndrome / Q000145:classification / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D008955:Models, Cardiovascular; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques
chemical_list: D017931:DNA Primers; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human