The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases

Pourrier, Marc; Fedida, David

doi:10.3390/ijms21020657

Cited by 39 publications

(25 citation statements)

References 188 publications

(248 reference statements)

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“…Patient-specific iPSC-CMs harboring other SCN5A mutations have been reported to be able to recapitulate cellular phenotypic features of BrS, such as reduced I Na , reduced maximal upstroke velocity of AP, increased burden of triggered activity, and abnormal Ca 2+ transients. [ 9 , 131 ]. For the SCN5A R1632C mutation carriers, in addition to clinical studies, an analysis of iPSC-CMs may promote the development of mutation-specific precision medicine.…”

Section: J Wave Syndrome (Brs and Ers)mentioning

confidence: 99%

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Nakajima

Tamura

Kurabayashi

et al. 2021

IJMS

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Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of β-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a unique mixed electrophysiological property of V392I-Kv4.3. Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy. Further studies using the iPSC technology may provide novel insights into the pathophysiology of atypical clinical phenotypes of IASs and the development of mutation-specific precision medicine.

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Section: J Wave Syndrome (Brs and Ers)mentioning

confidence: 99%

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Nakajima

Tamura

Kurabayashi

et al. 2021

IJMS

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“…However, limitations exist including significant electrophysiological differences between human and animal hearts, costs, as well as ethical considerations. To circumvent some of these shortcomings, cellular and multicellular models for arrhythmogenesis have been widely used, which are further enhanced by advances in human-induced pluripotent stem cells (hiPSCs), tissue engineering [14][15][16][17][18][19], and gene editing. The hiPSC-derived cardiomyocytes (hiPSC-CMs) can be obtained from healthy or diseased individuals, and provide the inexhaustible source for human disease modeling.…”

Section: Introductionmentioning

confidence: 99%

Model Systems for Addressing Mechanism of Arrhythmogenesis in Cardiac Repair

et al. 2021

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Purpose of Review Cardiac cell-based therapy represents a promising approach for cardiac repair. However, one of the main challenges is cardiac arrhythmias associated with stem cell transplantation. The current review summarizes the recent progress in model systems for addressing mechanisms of arrhythmogenesis in cardiac repair. Recent Findings Animal models have been extensively developed for mechanistic studies of cardiac arrhythmogenesis. Advances in human induced pluripotent stem cells (hiPSCs), patient-specific disease models, tissue engineering, and gene editing have greatly enhanced our ability to probe the mechanistic bases of cardiac arrhythmias. Additionally, recent development in multiscale computational studies and machine learning provides yet another powerful tool to quantitatively decipher the mechanisms of cardiac arrhythmias. Summary Advancing efforts towards the integrations of experimental and computational studies are critical to gain insights into novel mitigation strategies for cardiac arrhythmias in cell-based therapy.

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“…However, in BrS for instance, only in around 20-25% of the cases can a genetic diagnosis be obtained, leaving a large grey area of BrS patients without a clear pathogenetic mechanism [5]. Therefore, there is an urgent need for improved functional models and techniques to further aid in understanding the aetiology of ICA [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Optical Mapping in hiPSC-CM and Zebrafish to Resolve Cardiac Arrhythmias

Vandendriessche

Sieliwonczyk

Alaerts

et al. 2020

Hearts

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Inherited cardiac arrhythmias contribute substantially to sudden cardiac death in the young. The underlying pathophysiology remains incompletely understood because of the lack of representative study models and the labour-intensive nature of electrophysiological patch clamp experiments. Whereas patch clamp is still considered the gold standard for investigating electrical properties in a cell, optical mapping of voltage and calcium transients has paved the way for high-throughput studies. Moreover, the development of human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) has enabled the study of patient specific cell lines capturing the full genomic background. Nevertheless, hiPSC-CMs do not fully address the complex interactions between various cell types in the heart. Studies using in vivo models, are therefore necessary. Given the analogies between the human and zebrafish cardiovascular system, zebrafish has emerged as a cost-efficient model for arrhythmogenic diseases. In this review, we describe how hiPSC-CM and zebrafish are employed as models to study primary electrical disorders. We provide an overview of the contemporary electrophysiological phenotyping tools and discuss in more depth the different strategies available for optical mapping. We consider the current advantages and disadvantages of both hiPSC-CM and zebrafish as a model and optical mapping as phenotyping tool and propose strategies for further improvement. Overall, the combination of experimental readouts at cellular (hiPSC-CM) and whole organ (zebrafish) level can raise our understanding of the complexity of inherited cardiac arrhythmia disorders to the next level.

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The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases

Cited by 39 publications

References 188 publications

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Model Systems for Addressing Mechanism of Arrhythmogenesis in Cardiac Repair

Optical Mapping in hiPSC-CM and Zebrafish to Resolve Cardiac Arrhythmias

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