ArticleJournal of molecular and cellular cardiology2018
Hypertrophic cardiomyopathy-linked mutation in troponin T causes myofibrillar disarray and pro-arrhythmic action potential changes in human iPSC cardiomyocytes.
Article in Journal of molecular and cellular cardiology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 1 of them a synthesis that pooled it.
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Who cites it
56 citing papers in PubMed, 1 synthesis or guideline pooled it, 85 citations in OpenAlex.
- Cardiomyopathy phenotypes in human-induced pluripotent stem cell-derived cardiomyocytes-a systematic review.Pflugers Archiv : European journal of physiology · 2019Pooled it
- Associations between specific non-sustained ventricular tachycardia characteristics and sudden cardiac death in hypertrophic cardiomyopathy.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 · 2026Article
- Metabolic crisis and TRPM4 activation cause QT prolongation in TANGO2 deficiency disorder.Cardiovascular research · 2026Article
- Short SCN5A Transcript Yields a NaV1.5 Fragment Influencing Cardiac Metabolism.Circulation research · 2026Article
- Article
- Cardiomyocyte Nuclear Pleomorphism in a Mouse Model of Inherited Hypertrophic Cardiomyopathy.Journal of cardiovascular development and disease · 2025Article
- The role of the troponin T interactions with actin in regulation of cardiac thin filament revealed by the troponin T pathogenic variant Ile79Asn.Journal of molecular and cellular cardiology · 2025Article
- Induced Pluripotent Stem Cells in Cardiomyopathy: Advancing Disease Modeling, Therapeutic Development, and Regenerative Therapy.International journal of molecular sciences · 2025Review
- Experimental Models of Hypertrophic Cardiomyopathy: A Systematic Review.JACC. Basic to translational science · 2025Review
- Modeling the effects of thin filament near-neighbor cooperative interactions in mammalian myocardium.The Journal of general physiology · 2025Article
- Studying Pathogenetic Contribution of a Variant of Unknown Significance, p.M659I (c.1977G > A) in MYH7, to the Development of Hypertrophic Cardiomyopathy Using CRISPR/Cas9-Engineered Isogenic Induced Pluripotent Stem Cells.International journal of molecular sciences · 2024Article
- MYBPC3-c.772G>A mutation results in haploinsufficiency and altered myosin cycling kinetics in a patient induced stem cell derived cardiomyocyte model of hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology · 2024Article
- Harnessing molecular mechanism for precision medicine in dilated cardiomyopathy caused by a mutation in troponin T.bioRxiv : the preprint server for biology · 2024Article
- Assessing Cardiac Contractility From Single Molecules to Whole Hearts.JACC. Basic to translational science · 2024Review
- Article
- Maturation of iPSC-derived cardiomyocytes in a heart-on-a-chip device enables modeling of dilated cardiomyopathy caused by R222Q-SCN5A mutation.Biomaterials · 2023Article
- Molecular and cellular evidence for the impact of a hypertrophic cardiomyopathy-associated RAF1 variant on the structure and function of contractile machinery in bioartificial cardiac tissues.Communications biology · 2023Article
- Cardiac troponin T N-domain variant destabilizes the actin interface resulting in disturbed myofilament function.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Cellular and electrophysiological characterization of triadin knockout syndrome using induced pluripotent stem cell-derived cardiomyocytes.Stem cell reports · 2023Article
- Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.Circulation · 2023Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundMutations in cardiac troponin T (TnT) are linked to increased risk of ventricular arrhythmia and sudden death despite causing little to no cardiac hypertrophy. Studies in mice suggest that the hypertrophic cardiomyopathy (HCM)-associated TnT-I79N mutation increases myofilament Ca sensitivity and is arrhythmogenic, but whether findings from mice translate to human cardiomyocyte electrophysiology is not known.
objectivesTo study the effects of the TnT-I79N mutation in human cardiomyocytes.
methodsUsing CRISPR/Cas9, the TnT-I79N mutation was introduced into human induced pluripotent stem cells (hiPSCs). We then used the matrigel mattress method to generate single rod-shaped cardiomyocytes (CMs) and studied contractility, Ca handling and electrophysiology.
resultsCompared to isogenic control hiPSC-CMs, TnT-I79N hiPSC-CMs exhibited sarcomere disorganization, increased systolic function and impaired relaxation. The Ca-dependence of contractility was leftward shifted in mutation containing cardiomyocytes, demonstrating increased myofilament Ca sensitivity. In voltage-clamped hiPSC-CMs, TnT-I79N reduced intracellular Ca transients by enhancing cytosolic Ca buffering. These changes in Ca handling resulted in beat-to-beat instability and triangulation of the cardiac action potential, which are predictors of arrhythmia risk. The myofilament Ca sensitizer EMD57033 produced similar action potential triangulation in control hiPSC-CMs.
conclusionsThe TnT-I79N hiPSC-CM model not only reproduces key cellular features of TnT-linked HCM such as myofilament disarray, hypercontractility and diastolic dysfunction, but also suggests that this TnT mutation causes pro-arrhythmic changes of the human ventricular action potential.
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Registered trials
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.