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      Modeling Short QT Syndrome Using Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes

      research-article
      , MD 1 , 4 , , MD 1 , 4 , 8 , , PhD 4 , 5 , , MSc 1 , 4 , , MSc 1 , , MD 1 , , PhD 1 , 4 , , MD 1 , 4 , , MD 1 , , MD 4 , 6 , , MD 2 , 4 , , PhD 3 , 4 , , MD 7 , , MD 1 , 4 , , MD 1 , 4 , 8 , , , MD 1 , 4
      Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
      John Wiley and Sons Inc.
      arrhythmia (heart rhythm disorders), arrhythmia (mechanisms), ion channel, short QT syndrome, Arrhythmias, Sudden Cardiac Death, Electrophysiology, Cellular Reprogramming, Translational Studies

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          Abstract

          Background

          Short QT syndrome ( SQTS), a disorder associated with characteristic ECG QT‐segment abbreviation, predisposes affected patients to sudden cardiac death. Despite some progress in assessing the organ‐level pathophysiology and genetic changes of the disorder, the understanding of the human cellular phenotype and discovering of an optimal therapy has lagged because of a lack of appropriate human cellular models of the disorder. The objective of this study was to establish a cellular model of SQTS using human‐induced pluripotent stem cell–derived cardiomyocytes (hi PSCCMs).

          Methods and Results

          This study recruited 1 patient with short QT syndrome type 1 carrying a mutation (N588K) in KCNH2 as well as 2 healthy control subjects. We generated hi PSCs from their skin fibroblasts, and differentiated hi PSCs into cardiomyocytes (hi PSCCMs) for physiological and pharmacological studies. The hi PSCCMs from the patient showed increased rapidly activating delayed rectifier potassium channel current ( I K r) density and shortened action potential duration compared with healthy control hi PSCCMs. Furthermore, they demonstrated abnormal calcium transients and rhythmic activities. Carbachol increased the arrhythmic events in SQTS but not in control cells. Gene and protein expression profiling showed increased KCNH2 expression in SQTS cells. Quinidine but not sotalol or metoprolol prolonged the action potential duration and abolished arrhythmic activity induced by carbachol.

          Conclusions

          Patient‐specific hi PSCCMs are able to recapitulate single‐cell phenotype features of SQTS and provide novel opportunities to further elucidate the cellular disease mechanism and test drug effects.

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          Most cited references32

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          A high-efficiency system for the generation and study of human induced pluripotent stem cells.

          Direct reprogramming of human fibroblasts to a pluripotent state has been achieved through ectopic expression of the transcription factors OCT4, SOX2, and either cMYC and KLF4 or NANOG and LIN28. Little is known, however, about the mechanisms by which reprogramming occurs, which is in part limited by the low efficiency of conversion. To this end, we sought to create a doxycycline-inducible lentiviral system to convert primary human fibroblasts and keratinocytes into human induced pluripotent stem cells (hiPSCs). hiPSCs generated with this system were molecularly and functionally similar to human embryonic stem cells (hESCs), demonstrated by gene expression profiles, DNA methylation status, and differentiation potential. While expression of the viral transgenes was required for several weeks in fibroblasts, we found that 10 days was sufficient for the reprogramming of keratinocytes. Using our inducible system, we developed a strategy to induce hiPSC formation at high frequency. Upon addition of doxycycline to hiPSC-derived differentiated cells, we obtained "secondary" hiPSCs at a frequency at least 100-fold greater than the initial conversion. The ability to reprogram cells at high efficiency provides a unique platform to dissect the underlying molecular and biochemical processes that accompany nuclear reprogramming.
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            Sudden death associated with short-QT syndrome linked to mutations in HERG.

            Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers. We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.
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              Patient-Specific and Genome-Edited Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Brugada Syndrome.

              Brugada syndrome (BrS), a disorder associated with characteristic electrocardiogram precordial ST-segment elevation, predisposes afflicted patients to ventricular fibrillation and sudden cardiac death. Despite marked achievements in outlining the organ level pathophysiology of the disorder, the understanding of human cellular phenotype has lagged due to a lack of adequate human cellular models of the disorder.
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                Author and article information

                Contributors
                xiaobo.zhou@medma.uni-heidelberg.de
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                24 March 2018
                03 April 2018
                : 7
                : 7 ( doiID: 10.1002/jah3.2018.7.issue-7 )
                : e007394
                Affiliations
                [ 1 ] First Department of Medicine Faculty of Medicine University Medical Centre Mannheim (UMM) University of Heidelberg Mannheim Germany
                [ 2 ] Skin Cancer Unit German Cancer Research Center (DKFZ) Heidelberg and Department of Dermatology, Venereology and Allergology University Medical Center Mannheim University of Heidelberg Mannheim Germany
                [ 3 ] Institute of Experimental and Clinical Pharmacology and Toxicology Medical Faculty Mannheim University of Heidelberg Mannheim Germany
                [ 4 ] DZHK (German Center for Cardiovascular Research), Partner Sites Heidelberg‐Mannheim and Göttingen, Mannheim Germany
                [ 5 ] Stem Cell Unit Clinic for Cardiology and Pneumology University Medical Center Göttingen Germany
                [ 6 ] Institute of Pharmacology and Toxicology University of Göttingen Germany
                [ 7 ] Institute of Experimental Cardiovascular Medicine University Heart Centre Freiburg Bad Krozingen, Freiburg Germany
                [ 8 ] Key Laboratory of Medical Electrophysiology of Ministry of Education Institute of Cardiovascular Research Southwest Medical University Luzhou Sichuan China
                Author notes
                [*] [* ] Correspondence to: Xiao‐Bo Zhou, MD, First Department of Medicine, University Medical Centre Mannheim, Theodor‐Kutzer‐Ufer 1‐3, 68167 Mannheim, Germany. E‐mail: xiaobo.zhou@ 123456medma.uni-heidelberg.de
                [†]

                Dr El‐Battrawy and Dr Lan contributed equally to this work.

                Article
                JAH33012
                10.1161/JAHA.117.007394
                5907581
                29574456
                189f173b-0ca0-4805-ad85-e417d62d1704
                © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 12 August 2017
                : 26 January 2018
                Page count
                Figures: 9, Tables: 0, Pages: 14, Words: 8857
                Funding
                Funded by: DZHK (German Center for Cardiovascular Research)
                Funded by: BMBF (German Ministry of Education and Research)
                Categories
                Original Research
                Original Research
                Arrhythmia and Electrophysiology
                Custom metadata
                2.0
                jah33012
                03 April 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:03.04.2018

                Cardiovascular Medicine
                arrhythmia (heart rhythm disorders),arrhythmia (mechanisms),ion channel,short qt syndrome,arrhythmias,sudden cardiac death,electrophysiology,cellular reprogramming,translational studies

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