title: Human iPS cell model of type 3 long QT syndrome recapitulates drug-based phenotype correction.
abstract: Long QT syndrome is a potentially life-threatening disease characterized by delayed repolarization of cardiomyocytes, QT interval prolongation in the electrocardiogram, and a high risk for sudden cardiac death caused by ventricular arrhythmia. The genetic type 3 of this syndrome (LQT3) is caused by gain-of-function mutations in the SCN5A cardiac sodium channel gene which mediates the fast Nav1.5 current during action potential initiation. Here, we report the analysis of LQT3 human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). These were generated from a patient with a heterozygous p.R1644H mutation in SCN5A known to interfere with fast channel inactivation. LQT3 hiPSC-CMs recapitulated pathognomonic electrophysiological features of the disease, such as an accelerated recovery from inactivation of sodium currents as well as action potential prolongation, especially at low stimulation rates. In addition, unlike previously described LQT3 hiPSC models, we observed a high incidence of early after depolarizations (EADs) which is a trigger mechanism for arrhythmia in LQT3. Administration of specific sodium channel inhibitors was found to shorten action and field potential durations specifically in LQT3 hiPSC-CMs and antagonized EADs in a dose-dependent manner. These findings were in full agreement with the pharmacological response profile of the underlying patient and of other patients from the same family. Thus, our data demonstrate the utility of patient-specific LQT3 hiPSCs for assessing pharmacological responses to putative drugs and for improving treatment efficacies.
authors.affiliation: Institute of Physiology I, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Malan
authors.affiliation: Human Stem Cell Pluripotency Group, Max Planck Institute for Molecular Biomedicine, 48149, Münster, Germany.|Chemical Genomics Centre of the Max Planck Society, 44227, Dortmund, Germany.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, 48149, Münster, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Stallmeyer
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, 48149, Münster, Germany.
authors.forename: Jovanca
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institute of Physiology I, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, 48149, Münster, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.affiliation: Institute of Physiology I, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. philipp.sasse@uni-bonn.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Sasse
authors.affiliation: Human Stem Cell Pluripotency Group, Max Planck Institute for Molecular Biomedicine, 48149, Münster, Germany. boris.greber@mpi-muenster.mpg.de.|Chemical Genomics Centre of the Max Planck Society, 44227, Dortmund, Germany. boris.greber@mpi-muenster.mpg.de.
authors.forename: Boris
authors.initials: B
authors.lastname: Greber
mesh_terms: D000075224:Cardiac Conduction System Disease; D002478:Cells, Cultured; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010641:Phenotype
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
keywords: Cardiac disease modeling; Drug testing; Human iPS cells; Type 3 long-QT syndrome