ArticleThe Journal of general physiology2013
Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics.
Article in The Journal of general physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 108 papers.
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Who cites it
108 citing papers in PubMed, 198 citations in OpenAlex.
- The disease-specific phenotype in cardiomyocytes derived from induced pluripotent stem cells of two long QT syndrome type 3 patients.PloS one · 2013Trial
- The role of iPSC research for insight into inherited arrhythmia conditions.Heart rhythm · 2025Review
- Human induced pluripotent stem cell-derived cardiomyocytes for disease modeling and drug discovery.Frontiers in bioengineering and biotechnology · 2025Review
- Using induced pluripotent stem cells for drug discovery in arrhythmias.Expert opinion on drug discovery · 2024Review
- The occurrence and development of induced pluripotent stem cells.Frontiers in genetics · 2024Review
- Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Beneficial effects of chronic mexiletine treatment in a human model of SCN5A overlap syndrome.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Unlocking the potential of induced pluripotent stem cells for neonatal disease modeling and drug development.Seminars in perinatology · 2023Review
- iPSC-Derived Cardiomyocytes in Inherited Cardiac Arrhythmias: Pathomechanistic Discovery and Drug Development.Biomedicines · 2023Review
- Precision medicine for long QT syndrome: patient-specific iPSCs take the lead.Expert reviews in molecular medicine · 2023Review
- Human-Induced Pluripotent Stem Cell-Based Differentiation of Cardiomyocyte Subtypes for Drug Discovery and Cell Therapy.Handbook of experimental pharmacology · 2023Article
- Exploring mutation specific beta blocker pharmacology of the pathogenic late sodium channel current from patient-specific pluripotent stem cell myocytes derived from long QT syndrome mutation carriers.Channels (Austin, Tex.) · 2022Article
- Translational potential of hiPSCs in predictive modeling of heart development and disease.Birth defects research · 2022Review
- Deconvoluting the Cells of the Human Heart with iPSC Technology: Cell Types, Protocols, and Uses.Current cardiology reports · 2022Review
- Deciphering Common Long QT Syndrome Using CRISPR/Cas9 in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.Frontiers in cardiovascular medicine · 2022Review
- Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.Clinical and translational medicine · 2021Review
- Review
- Human-induced pluripotent stem cell-derived cardiomyocytes: Cardiovascular properties and metabolism and pharmacokinetics of deuterated mexiletine analogs.Pharmacology research & perspectives · 2021Article
- Human-induced pluripotent stem cells as models for rare cardiovascular diseases: from evidence-based medicine to precision medicine.Pflugers Archiv : European journal of physiology · 2021Review
- Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.International journal of molecular sciences · 2021Article
48 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was found to have a de novo SCN5A LQT-3 mutation (F1473C) and a polymorphism (K897T) in KCNH2, the gene for LQT-2. Analysis of the biophysics and molecular pharmacology of ion channels expressed in cardiomyocytes (CMs) differentiated from these iPSCs (iPSC-CMs) demonstrates a primary LQT-3 (Na(+) channel) defect responsible for the arrhythmias not influenced by the KCNH2 polymorphism. The F1473C mutation occurs in the channel inactivation gate and enhances late Na(+) channel current (I(NaL)) that is carried by channels that fail to inactivate completely and conduct increased inward current during prolonged depolarization, resulting in delayed repolarization, a prolonged QT interval, and increased risk of fatal arrhythmia. We find a very pronounced rate dependence of I(NaL) such that increasing the pacing rate markedly reduces I(NaL) and, in addition, increases its inhibition by the Na(+) channel blocker mexiletine. These rate-dependent properties and drug interactions, unique to the proband's iPSC-CMs, correlate with improved management of arrhythmias in the patient and provide support for this approach in developing patient-specific clinical regimens.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.