Dantrolene rescues arrhythmogenic RYR2 defect in a patient‐specific stem cell model of catecholaminergic polymorphic ventricular tachycardia
Christian B. Jung,Alessandra Moretti,Michael Mederos y Schnitzler,Laura Iop,Ursula Storch,Milena Bellin,Tatjana Dorn,Sandra Ruppenthal,Sarah Pfeiffer,Alexander Goedel,Ralf J. Dirschinger,Melchior Seyfarth,Jason T. Lam,Daniel Sinnecker,Thomas Gudermann,Peter Lipp,Karl-Ludwig Laugwitz +16 more
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TLDR
The generation of induced pluripotent stem cells (iPSCs) from a CPVT patient carrying a novel RYR2 S406L mutation provides a new in vitro model to study the pathogenesis of human cardiac arrhythmias and develop novel therapies for CPVT.Abstract:
Coordinated release of calcium (Ca2+) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress-induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca2+ release from the SR causing arrhythmogenic delayed after depolarizations (DADs). Here, we report the generation of induced pluripotent stem cells (iPSCs) from a CPVT patient carrying a novel RYR2 S406L mutation. In patient iPSC-derived cardiomyocytes, catecholaminergic stress led to elevated diastolic Ca2+ concentrations, a reduced SR Ca2+ content and an increased susceptibility to DADs and arrhythmia as compared to control myocytes. This was due to increased frequency and duration of elementary Ca2+ release events (Ca2+ sparks). Dantrolene, a drug effective on malignant hyperthermia, restored normal Ca2+ spark properties and rescued the arrhythmogenic phenotype. This suggests defective inter-domain interactions within the RYR2 channel as the pathomechanism of the S406L mutation. Our work provides a new in vitro model to study the pathogenesis of human cardiac arrhythmias and develop novel therapies for CPVT.read more
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Drug Screening Using a Library of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes Reveals Disease-Specific Patterns of Cardiotoxicity
Ping Liang,Feng Lan,Andrew S. Lee,Tingyu Gong,Veronica Sanchez-Freire,Yongming Wang,Sebastian Diecke,Karim Sallam,Joshua W. Knowles,Paul J. Wang,Patricia K. Nguyen,Donald M. Bers,Robert C. Robbins,Joseph C. Wu +13 more
TL;DR: The data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human ether-a-go-go–related gene test or healthy control hiPSc-CM/hESC-CM screening assays.
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Engineered in vitro disease models.
Kambez H. Benam,Stephanie Dauth,Bryan Hassell,Anna Herland,Abhishek Jain,Kyung-Jin Jang,Katia Karalis,Katia Karalis,Hyun-Jung Kim,Luke A. MacQueen,Roza Mahmoodian,Samira Musah,Yu Suke Torisawa,Andries D. van der Meer,Remi Villenave,Moran Yadid,Kevin Kit Parker,Donald E. Ingber +17 more
TL;DR: E engineered in vitro models of diseases of the heart, lung, intestine, liver, kidney, cartilage, skin and vascular, endocrine, musculoskeletal, and nervous systems, as well as models of infectious diseases and cancer are provided.
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Induced pluripotent stem cells: the new patient?
TL;DR: For example, patient-specific induced pluripotent stem (iPS) cells are an emerging paradigm that may address the difficulty in modelling human diseases in laboratory assays or experimental animals as discussed by the authors.
Journal ArticleDOI
Calcium Signaling and Cardiac Arrhythmias.
TL;DR: The key role of Ca2+ in normal cardiac function-in particular, excitation-contraction coupling and normal electric rhythms is reviewed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2-handling proteins.
Journal ArticleDOI
Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Insights into Molecular, Cellular, and Functional Phenotypes
TL;DR: Patient-specific iPSC-derived cardiomyocytes offer an attractive experimental platform to model cardiovascular diseases, study the earliest stages of human development, accelerate predictive drug toxicology tests, and advance potential regenerative therapies.
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