Probing flecainide block of I using human pluripotent stem cell-derived ventricular cardiomyocytes adapted to automated patch-clamping and 2D monolayers

Geng, Lin; Kong, Chi-Wing; Wong, Andy O.-T.; Shum, A.; Chow, Maggie Zi Ying; Che, Hui; Zhang, Chenzi; Yau, Ka-Long; Chan, Chun Man; Keung, Wendy; Tse, Gary

doi:10.1016/j.toxlet.2018.05.006

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…Although the principles are easy to understand, at present there are some important caveats. One is that fibroblast generated iPSCs demonstrate an immature phenotype so that they more closely resemble mid-gestation human fetal hearts[ 71 - 73 ]. These differences may well alter final experimental and clinical results, depending on the stage of development of the iPSCs being used.…”

Section: Discussionmentioning

confidence: 99%

Role of induced pluripotent stem cells in diagnostic cardiology

Karch¹,

Fineschi²,

Francia³

et al. 2021

WJSC

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Ethical concerns about stem cell-based research have delayed important advances in many areas of medicine, including cardiology. The introduction of induced pluripotent stem cells (iPSCs) has supplanted the need to use human stem cells for most purposes, thus eliminating all ethical controversies. Since then, many new avenues have been opened in cardiology research, not only in approaches to tissue replacement but also in the design and testing of antiarrhythmic drugs. This methodology has advanced to the point where induced human cardiomyocyte cell lines can now also be obtained from commercial sources or tissue banks. Initial studies with readily available iPSCs have generally confirmed that their behavioral characteristics accurately predict the behavior of beating cardiomyocytes in vivo . As a result, iPSCs can provide new ways to study arrhythmias and heart disease in general, accelerating the development of new, more effective antiarrhythmic drugs, clinical diagnoses, and personalized medical care. The focus on producing cardiomyocytes that can be used to replace damaged heart tissue has somewhat diverted interest in a host of other applications. This manuscript is intended to provide non-specialists with a brief introduction and overview of the research carried out in the field of heart rhythm disorders.

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Section: Discussionmentioning

confidence: 99%

Role of induced pluripotent stem cells in diagnostic cardiology

Karch¹,

Fineschi²,

Francia³

et al. 2021

WJSC

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“…With the Courtemanche-Ramirez-Nattel model ( Courtemanche et al, 1998 ; Sossalla et al, 2010 ; Grandi et al, 2011 ) as the baseline, the effects of flecainide were implemented by applying the percent changes for the specific ion channels. Compared with baseline AF, the I to , I CaL , I Kr , and I Na were decreased by 5, 5, 30 and 45%, respectively ( Wang et al, 1993 ; Hilliard et al, 2010 ; Kramer et al, 2013 ; Crumb et al, 2016 ; Geng et al, 2018 ; Sutanto et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Anti-atrial Fibrillation Effects of Pulmonary Vein Isolation With or Without Ablation Gaps: A Computational Modeling Study

et al. 2022

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BackgroundAlthough pulmonary vein isolation (PVI) gaps contribute to recurrence after atrial fibrillation (AF) catheter ablation, the mechanism is unclear. We used realistic computational human AF modeling to explore the AF wave-dynamic changes of PVI with gaps (PVI-gaps).MethodsWe included 40 patients (80% male, 61.0 ± 9.8 years old, 92.5% persistent AF) who underwent AF catheter ablation to develop our realistic computational AF model. We compared the effects of a complete PVI (CPVI) and PVI-gap (2-mm × 4) on the AF wave-dynamics by evaluating the dominant frequency (DF), spatial change of DF, maximal slope of the action potential duration restitution curve (Smax), and AF defragmentation rate (termination or change to atrial tachycardia), and tested the effects of additional virtual interventions and flecainide on ongoing AF with PVI-gaps.ResultsCompared with the baseline AF, CPVIs significantly reduced extra-PV DFs (p < 0.001), but PVI-gaps did not. COV-DFs were greater after CPVIs than PVI-gaps (p < 0.001). Neither CPVIs nor PVI-gaps changed the mean Smax. CPVIs resulted in higher AF defragmentation rates (80%) than PVI-gaps (12.5%, p < 0.001). In ongoing AF after PVI-gaps, the AF defragmentation rates after a wave-breaking gap ablation, extra-PV DF ablation, or flecainide were 60.0, 34.3, and 25.7%, respectively (p = 0.010).ConclusionCPVIs effectively reduced the DF, increased its spatial heterogeneity in extra-PV areas, and offered better anti-AF effects than extra-PV DF ablation or additional flecainide in PVI-gap conditions.

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“…Atrial-specific cardiomyocytes have been used to assess atrial selectivity and efficacy of antiarrhythmic drugs [ 99 , 100 ]. Drug-induced arrhythmia has also been tested with ventricular-like cardiomyocytes [ 101 ].…”

Section: Strategies For Using Ipsc-based Models For Disease Modelling and Drug Testingmentioning

confidence: 99%

Application of Patient-Specific iPSCs for Modelling and Treatment of X-Linked Cardiomyopathies

Zhang

Chou

Tse

et al. 2021

IJMS

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Inherited cardiomyopathies are among the major causes of heart failure and associated with significant mortality and morbidity. Currently, over 70 genes have been linked to the etiology of various forms of cardiomyopathy, some of which are X-linked. Due to the lack of appropriate cell and animal models, it has been difficult to model these X-linked cardiomyopathies. With the advancement of induced pluripotent stem cell (iPSC) technology, the ability to generate iPSC lines from patients with X-linked cardiomyopathy has facilitated in vitro modelling and drug testing for the condition. Nonetheless, due to the mosaicism of the X-chromosome inactivation, disease phenotypes of X-linked cardiomyopathy in heterozygous females are also usually more heterogeneous, with a broad spectrum of presentation. Recent advancements in iPSC procedures have enabled the isolation of cells with different lyonisation to generate isogenic disease and control cell lines. In this review, we will summarise the current strategies and examples of using an iPSC-based model to study different types of X-linked cardiomyopathy. The potential application of isogenic iPSC lines derived from a female patient with heterozygous Danon disease and drug screening will be demonstrated by our preliminary data. The limitations of an iPSC-derived cardiomyocyte-based platform will also be addressed.

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Probing flecainide block of I using human pluripotent stem cell-derived ventricular cardiomyocytes adapted to automated patch-clamping and 2D monolayers

Cited by 7 publications

References 26 publications

Role of induced pluripotent stem cells in diagnostic cardiology

Role of induced pluripotent stem cells in diagnostic cardiology

Anti-atrial Fibrillation Effects of Pulmonary Vein Isolation With or Without Ablation Gaps: A Computational Modeling Study

Application of Patient-Specific iPSCs for Modelling and Treatment of X-Linked Cardiomyopathies

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