Modeling of Catecholaminergic Polymorphic Ventricular Tachycardia With Patient-Specific Human-Induced Pluripotent Stem Cells

Itzhaki, Ilanit; Maizels, Leonid; Huber, Irit; Gepstein, Amira; Arbel, Gil; Caspi, Oren; Miller, Liron; Belhassen, Bernard; Nof, Eyal; Glikson, Michael; Gepstein, Lior

doi:10.1016/j.jacc.2012.02.066

Cited by 200 publications

(161 citation statements)

References 27 publications

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“…7,8 In the cardiac field, hiPSCs were established from healthy individuals and from patients inflicted with acquired 9 and several types of inherited cardiac disorders. 10,11 Patient-specific hiPSC-derived cardiomyocyte (hiPSC-CM) models of different inherited arrhythmogenic syndromes (including the long-QT, [12][13][14][15] Brugada, 16 and sodium channel overlap 17 syndromes; arrhythmogenic right ventricular cardiomyopathy 18,19 ; and both types of CPVT [20][21][22][23][24][25][26][27][28][29] ) were…”

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confidence: 99%

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

Maizels

Huber

Arbel

et al. 2017

Circ: Arrhythmia and Electrophysiology

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Background-Catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) results from autosomal recessive CASQ2 mutations, causing abnormal Ca 2+ -handling and malignant ventricular arrhythmias. We aimed to establish a patient-specific human induced pluripotent stem cell (hiPSC) model of CPVT2 and to use the generated hiPSC-derived cardiomyocytes to gain insights into patient-specific disease mechanism and pharmacotherapy. Methods and Results-hiPSC cardiomyocytes were derived from a CPVT2 patient (D307H-CASQ2 mutation) and from healthy controls. Laser-confocal Ca 2+ and voltage imaging showed significant Ca 2+ -transient irregularities, marked arrhythmogenicity manifested by early afterdepolarizations and triggered arrhythmias, and reduced threshold for store overload-induced Ca 2+ -release events in the CPVT2-hiPSC cardiomyocytes when compared with healthy control cells. Pharmacological studies revealed the prevention of adrenergic-induced arrhythmias by β-blockers (propranolol and carvedilol), flecainide, and the neuronal sodium-channel blocker riluzole; a direct antiarrhythmic action of carvedilol (independent of its α/β-adrenergic blocking activity), flecainide, and riluzole; and suppression of abnormal Ca 2+ cycling by the ryanodine stabilizer JTV-519 and carvedilol. Mechanistic insights were gained on the different antiarrhythmic actions of the aforementioned drugs, with carvedilol and JTV-519 (but not flecainide or riluzole) acting primarily through sarcoplasmic reticulum stabilization. Finally, comparable outcomes were found between flecainide and labetalol antiarrhythmic effects in vitro and the clinical results in the same patient.Conclusions-These results demonstrate the ability of hiPSCs cardiomyocytes to recapitulate CPVT2 disease phenotype and drug response in the culture dish, to provide novel insights into disease and drug therapy mechanisms, and potentially to tailor patient-specific drug therapy. (Circ Arrhythm Electrophysiol. 2017;10:e004725.

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Section: See Editorial By LI Et Almentioning

confidence: 99%

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

Maizels

Huber

Arbel

et al. 2017

Circ: Arrhythmia and Electrophysiology

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“…15 In the current study, we aimed to use the emerging hiPSC technology to establish an in vitro model of ARVC. We Background-Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disorder resulting from desmosomal protein mutations.…”

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confidence: 99%

Modeling of Arrhythmogenic Right Ventricular Cardiomyopathy With Human Induced Pluripotent Stem Cells

Caspi

Huber

Gepstein

et al. 2013

Circ Cardiovasc Genet

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dilated and hypertrophic cardiomyopathies, 13,14 and cathecolaminergic polymorphic ventricular tachycardia. 15 In the current study, we aimed to use the emerging hiPSC technology to establish an in vitro model of ARVC. We Background-Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disorder resulting from desmosomal protein mutations. ARVC is characterized pathologically by fibrofatty infiltration and clinically by arrhythmias and sudden cardiac death. We aimed to establish a patient-/disease-specific human induced pluripotent stem cell (hiPSC) model of ARVC. Methods and Results-Dermal fibroblasts were obtained from 2 patients with ARVC with plakophilin-2 (PKP2) mutations, reprogrammed to generate hiPSCs, coaxed to differentiate into cardiomyocytes (CMs), and then compared with healthy control hiPSC-derived CMs (hiPSC-CMs). Real-time polymerase chain reaction showed a significant decrease in the expression of PKP2 in the ARVC-hiPSC-CMs. Immunostainings revealed reduced densities of PKP2, the associated desmosomal protein plakoglobin, and the gap-junction protein connexin-43. Electrophysiological assessment demonstrated prolonged field potential rise time in the ARVC-hiPSC-CMs. Transmission electron microscopy identified widened and distorted desmosomes in the ARVC-hiPSC-CMs. Clusters of lipid droplets were identified in the ARVC-CMs that displayed the more severe desmosomal pathology. This finding was associated with upregulation of the proadipogenic transcription factor peroxisome proliferator-activated receptor-γ. Exposure of the cells to apidogenic stimuli augmented desmosomal distortion and lipid accumulation. The latter phenomenon was prevented by application of a specific inhibitor of glycogen synthase kinase 3β (6-bromoindirubin-3'-oxime). Conclusions-This study highlights the unique potential of the hiPSC technology for modeling inherited cardiac disorders in general and ARVC specifically. The hiPSC-CMs were demonstrated to recapitulate the ARVC phenotype in the dish, provide mechanistic insights into early disease pathogenesis, and provide a unique platform for drug discovery and testing in this disorder.

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“…Electrophysiological analysis of these cells revealed a heterogeneous population comprising cells with nodal, atrial, and ventricular profiles (data not shown, Priori, S.G., et al, J. Clin. Invest., In Press, 14,15,20 ). …”

Section: Representative Resultsmentioning

confidence: 99%

Generation of Human Cardiomyocytes: A Differentiation Protocol from Feeder-free Human Induced Pluripotent Stem Cells

Pasquale

Song

Condorelli

2013

JoVE

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In order to investigate the events driving heart development and to determine the molecular mechanisms leading to myocardial diseases in humans, it is essential first to generate functional human cardiomyocytes (CMs). The use of these cells in drug discovery and toxicology studies would also be highly beneficial, allowing new pharmacological molecules for the treatment of cardiac disorders to be validated pre-clinically on cells of human origin. Of the possible sources of CMs, induced pluripotent stem (iPS) cells are among the most promising, as they can be derived directly from readily accessible patient tissue and possess an intrinsic capacity to give rise to all cell types of the body 1 . Several methods have been proposed for differentiating iPS cells into CMs, ranging from the classical embryoid bodies (EBs) aggregation approach to chemically defined protocols 2,3 . In this article we propose an EBs-based protocol and show how this method can be employed to efficiently generate functional CM-like cells from feeder-free iPS cells. Video LinkThe video component of this article can be found at

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Modeling of Catecholaminergic Polymorphic Ventricular Tachycardia With Patient-Specific Human-Induced Pluripotent Stem Cells

Abstract: This study highlights the potential of hiPSCs for studying inherited arrhythmogenic syndromes, in general, and CPVT specifically. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care, and aid in the development of new therapies.

Cited by 200 publications

References 27 publications

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

Modeling of Arrhythmogenic Right Ventricular Cardiomyopathy With Human Induced Pluripotent Stem Cells

Generation of Human Cardiomyocytes: A Differentiation Protocol from Feeder-free Human Induced Pluripotent Stem Cells

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