Ion Channel Dysfunctions in Dilated Cardiomyopathy in Limb-Girdle Muscular Dystrophy

El‐Battrawy, Ibrahim; Zhao, Zhihan; Liu, Huan; Li, Xin; Yücel, Gökhan; Lang, Siegfried; Sattler, Katherine; Schünemann, Jan-Dierk; Zimmermann, Wolfram‐Hubertus; Cyganek, Lukas; Utikal, Jochen; Wieland, Thomas; Bieback, Karen; Bauer, Ralf; Ratte, Antonius; Pribe-Wolferts, Regina; Rapti, Kleopatra; Nowak, Daniel; Wittig, Janina; Thomas, Dierk; Most, Patrick; Katus, Hugo A.; Ravens, Ursula; Schmidt, Constanze; Borggrefe, Martin; Zhou, Xiaobo; Müller, Oliver; Akın, İbrahim

doi:10.1161/circgen.117.001893

Cited by 43 publications

(40 citation statements)

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“…This animal model is not ideal, either, because the differences between animals and humans—as well as the differences between the drug‐induced SQTS and disease‐induced SQTS—may influence the results of drug testing. Our group has successfully used human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) to model some key features of different diseases, including SQTS1 . We have demonstrated that the hiPSC‐CMs from an SQTS1 patient (SQTS1 hiPSC‐CMs) are able to recapitulate the single‐cell phenotypic features of SQTS (APD‐shortening and arrhythmic calcium transients) and provide novel opportunities to further elucidate the disease mechanism and test drug effects …”

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confidence: 99%

“…Our group has successfully used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model some key features of different diseases, including SQTS1. [22][23][24][25][26][27][28] We have demonstrated that the hiPSC-CMs from an SQTS1 patient (SQTS1 hiPSC-CMs) are able to recapitulate the single-cell phenotypic features of SQTS (APDshortening and arrhythmic calcium transients) and provide novel opportunities to further elucidate the disease mechanism and test drug effects. 27 Therefore, we designed the current study to examine the APDprolonging and antiarrhythmic effects of some drugs using our well-defined and characterized model of SQTS1.…”

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confidence: 99%

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Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Zhao

El‐Battrawy

et al. 2019

Clin Pharma and Therapeutics

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Short QT syndrome (SQTS) predisposes afflicted patients to sudden cardiac death. Until now, only one drug—quinidine—has been shown to be effective in patients with SQTS type 1(SQTS1). The objective of this study was to use human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) from a patient with SQTS1 to search for potentially effective drugs for the treatment of SQTS1 patients. Patch clamp and single‐cell contraction measurements were employed to assess drug effects. Ivabradine, mexiletine, and ajmaline but not flecainide, ranolazine, or amiodarone prolonged the action potential duration (APD) in hiPSC‐CMs from an SQTS1 patient. Ivabradine, ajmaline, and mexiletine inhibited KCNH2 channel currents significantly, which may underlie their APD‐prolonging effects. Under proarrhythmic epinephrine stimulation in spontaneously beating SQTS1 hiPSC‐CMs, ivabradine, mexiletine, and ajmaline but not flecainide reduced the epinephrine‐induced arrhythmic events. The results demonstrate that ivabradine, ajmaline, and mexiletine may be candidate drugs for preventing tachyarrhythmias in SQTS1 patients.

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confidence: 99%

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confidence: 99%

Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Zhao

El‐Battrawy

et al. 2019

Clin Pharma and Therapeutics

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“…11:e001893. El-Battrawy et al (2018) [ 52 ] DM1 Disease modeling Cell Reprogram. 15:237–48 Xia (2013) [ 53 ] DM1 Therapeutic genome editing Stem Cells.…”

Section: Human Ipsc As Models For Disease Mechanism Studies and Drug mentioning

confidence: 99%

“…The detailed molecular or electrophysiological mechanism is not defined because of the difficulties of accessing live human cardiac cells and animal models failed to demonstrate cardiomyopathy [ 83 ]. A recent study using human iPSC model shed light on the pathogenesis [ 52 ]. The author found that human iPSC-derived cardiomyocytes from a patient with LGMD2I (patient also has dilated cardiomyopathy associated with recurrent ventricular tachycardia) exhibited sodium, calcium, and K+ channel dysfunction, leading to reduced amplitude and upstroke velocity of action potentials as well as diminished Ca 2+ release.…”

Section: Human Ipsc As Models For Disease Mechanism Studies and Drug mentioning

confidence: 99%

Human iPSC Models to Study Orphan Diseases: Muscular Dystrophies

2018

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Purpose of ReviewMuscular dystrophies (MDs) are a spectrum of muscle disorders, which are caused by a number of gene mutations. The studies of MDs are limited due to lack of appropriate models, except for Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), facioscapulohumeral muscular dystrophy (FSHD), and certain type of limb-girdle muscular dystrophy (LGMD). Human induced pluripotent stem cell (iPSC) technologies are emerging to offer a useful model for mechanistic studies, drug discovery, and cell-based therapy to supplement in vivo animal models. This review will focus on current applications of iPSC as disease models of MDs for studies of pathogenic mechanisms and therapeutic development.Recent FindingsMany and more human disease-specific iPSCs have been or being established, which carry the natural mutation of MDs with human genomic background. These iPSCs can be differentiated into specific cell types affected in a particular MDs such as skeletal muscle progenitor cells, skeletal muscle fibers, and cardiomyocytes. Human iPSCs are particularly useful for studies of the pathogenicity at the early stage or developmental phase of MDs. High-throughput screening using disease-specific human iPSCs has become a powerful technology in drug discovery. While MD iPSCs have been generated for cell-based replacement therapy, recent advances in genome editing technologies enabled correction of genetic mutations in these cells in culture, raising hope for in vivo genome therapy, which offers a fundamental cure for these daunting inherited MDs.SummaryHuman disease-specific iPSC models for MDs are emerging as an additional tool to current disease models for elucidating disease mechanisms and developing therapeutic intervention.

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“…In addition, substantial interline variability in cardiac differentiation capacity exists, emphasizing the need for reliable controls. Nevertheless, hiPSCs have been successfully used to model several cardiovascular diseases ( Brandao et al., 2017 ; El-Battrawy et al., 2018 ; Goedel et al., 2017 ; Moretti et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Precise Correction of Heterozygous SHOX2 Mutations in hiPSCs Derived from Patients with Atrial Fibrillation via Genome Editing and Sib Selection

et al. 2020

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Summary Patient-specific human induced pluripotent stem cells (hiPSCs) offer unprecedented opportunities for the investigation of multigenic disease, personalized medicine, and stem cell therapy. For heterogeneous diseases such as atrial fibrillation (AF), however, precise correction of the associated mutation is crucial. Here, we generated and corrected hiPSC lines from two AF patients carrying different heterozygous SHOX2 mutations. We developed a strategy for the scarless correction of heterozygous mutations, based on stochastic enrichment by sib selection, followed by allele quantification via digital PCR and next-generation sequencing to detect isogenic subpopulations. This allowed enriching edited cells 8- to 20-fold. The method does not require antibiotic selection or cell sorting and can be easily combined with base-and-prime editing approaches. Our strategy helps to overcome low efficiencies of homology-dependent repair in hiPSCs and facilitates the generation of isogenic control lines that represent the gold standard for modeling complex diseases in vitro .

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Ion Channel Dysfunctions in Dilated Cardiomyopathy in Limb-Girdle Muscular Dystrophy

Cited by 43 publications

References 45 publications

Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Human iPSC Models to Study Orphan Diseases: Muscular Dystrophies

Precise Correction of Heterozygous SHOX2 Mutations in hiPSCs Derived from Patients with Atrial Fibrillation via Genome Editing and Sib Selection

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