scholarly journals Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

2013 ◽  
Vol 200 (1) ◽  
pp. i3-i3 ◽  
Author(s):  
Cecile Terrenoire ◽  
Kai Wang ◽  
Kelvin W. Chan Tung ◽  
Wendy K. Chung ◽  
Robert H. Pass ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cells ◽  
Long Qt ◽  
Complex Genetics ◽  
Drug Actions ◽  
Qt Syndrome ◽  
Induced Pluripotent

scholarly journals Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

2012 ◽  
Vol 141 (1) ◽  
pp. 61-72 ◽  
Author(s):  
Cecile Terrenoire ◽  
Kai Wang ◽  
Kelvin W. Chan Tung ◽  
Wendy K. Chung ◽  
Robert H. Pass ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cells ◽  
Na Channel ◽  
Long Qt ◽  
Complex Genetics ◽  
Drug Actions ◽  
Qt Syndrome ◽  
Induced Pluripotent

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 (INaL) 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 INaL such that increasing the pacing rate markedly reduces INaL 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.

scholarly journals From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2

2019 ◽  
Vol 40 (23) ◽  
pp. 1832-1836 ◽  
Author(s):  
Peter J Schwartz ◽  
Massimiliano Gnecchi ◽  
Federica Dagradi ◽  
Silvia Castelletti ◽  
Gianfranco Parati ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cells ◽  
Patient Specific ◽  
Syndrome Type ◽  
Long Qt ◽  
Qt Syndrome ◽  
Induced Pluripotent

Modelling the long QT syndrome with induced pluripotent stem cells

Nature ◽  
2011 ◽  
Vol 471 (7337) ◽  
pp. 225-229 ◽  
Author(s):  
Ilanit Itzhaki ◽  
Leonid Maizels ◽  
Irit Huber ◽  
Limor Zwi-Dantsis ◽  
Oren Caspi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cells ◽  
Long Qt ◽  
Qt Syndrome ◽  
Induced Pluripotent

scholarly journals Long QT Syndrome Modelling with Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells

2019 ◽  
Vol 8 (2) ◽  
pp. 105-110 ◽  
Author(s):  
Luca Sala ◽  
Massimiliano Gnecchi ◽  
Peter J Schwartz
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cells ◽  
Cardiac Electrophysiology ◽  
Clinical Decision Making ◽  
Long Qt ◽  
Qt Syndrome ◽  
Induced Pluripotent

Long QT syndrome (LQTS) is a potentially severe arrhythmogenic disorder, associated with a prolonged QT interval and sudden death, caused by mutations in key genes regulating cardiac electrophysiology. Current strategies to study LQTS in vitro include heterologous systems or animal models. Despite their value, the overwhelming power of genetic tools has exposed the many limitations of these technologies. In 2010, human-induced pluripotent stem cells (hiPSCs) revolutionised the field and allowed scientists to study in vitro some of the disease traits of LQTS on hiPSC-derived cardiomyocytes (hiPSC-CMs) from LQTS patients. In this concise review we present how the hiPSC technology has been used to model three main forms of LQTS and the severe form of LQTS associated with mutations in calmodulin. We also introduce some of the most recent challenges that must be tackled in the upcoming years to successfully shift hiPSC-CMs from powerful in vitro disease modelling tools into assets to improve risk stratification and clinical decision-making.

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