Impedance-Based Detection of Beating Rhythm and Proarrhythmic Effects of Compounds on Stem Cell-Derived Cardiomyocytes

Jonsson, Malin K.B.; Wang, Qingdong; Becker, Bruno

doi:10.1089/adt.2011.0396

Cited by 90 publications

(73 citation statements)

References 32 publications

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“…Together, these results are consistent with ILK-mediated, SERCA-2a-and pPLN-dependent increased rate of SR calcium uptake. The long-term (410 days) beat rate response to the SERCA inhibitor TG in iPSC-CMs was determined by measurements of electrical impedance using the xCELLigence RTCA Cardio System 46,47 . Consistent with the calcium transient profiles, transduction of ILK WT resulted in a faster baseline cardiomyocyte firing rate compared with untreated cells and to vector-only transduced controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca 2 þ ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILK R211A ) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.

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Section: Resultsmentioning

confidence: 99%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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“…The non-dividing cells must be kept in standard culture conditions for 2 -3 weeks before 3 Compounds decreasing frequency 11% -20% (n = 6) ordered alphabetically: benzydamine, dorzolamide, maprotiline, strychnine, tacrine, tropisetron. 4 Compounds decreasing frequency 6% -10% (n = 10) ordered alphabetically: aripiprazole, bumetanide, cyclosporine, granisetron, hydroxytacrine, mepyramine, mesoridazine, methiothepin, neostigmine, primaquine.…”

Section: Discussionmentioning

confidence: 99%

“…PDE inhibitors are markedly subtype-specific: PDE4 inhibitors (selective or not) accelerate rhythm whereas other subtype inhibitors (1,2,3,5,6) are inactive, except for high concentrations of PDE3 or PDE5 inhibitors. This indicates that PDE4 is of particular importance in controlling hiPSC-CM beating frequency.…”

Section: Discussionmentioning

confidence: 99%

“…Human induced pluripotent stem cells (hiPSC) can differentiate into functional cardiomyocytes [1] and bio-engineering technologies can produce and reliably supply large quantities of isolated cells that are Open Access J. Biomedical Science and Engineering highly enriched in functional cardiomyocytes, as evidenced by their phenotypic and electrophysiological characteristics, and that develop into spontaneously-beating syncytia in-vitro [2][3][4]. These hiPSC-derived cardiomyocytes (hiPSC-CM) are likely to provide an ideal source of human cells to generate models for drug development, particularly when questions arise regarding cardiac effects that may be seen when a drug is administered to humans.…”

Section: Introductionmentioning

confidence: 99%

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Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Sube¹,

Ertel²

2017

JBiSE

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Introduction: Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) form spontaneously beating syncytia in-vitro. We evaluated whether hiPSC-CM are a compelling model of human cardiac pharmacology useful for early drug development. Methods: We measured hiPSC-CM beating frequency using Ca-sensitive dyes and a high-throughput screening system. We quantified the effects of 640 drugs with various structures and pharmacologies. Results: When tested at 1 µM, most drugs without direct effects on heart rhythm or with effects at high concentrations do not change frequency, indicating specificity. In contrast, the preparation detects compounds with direct activity on heart rhythm, demonstrating sensitivity. In particular, β-adrenergic agonists increase frequency and the model differentiates β2 from β1 agonists, as well as partial from full agonists. Phosphodiesterase inhibitors have subtype-specific actions and PDE4 is particularly important in controlling frequency. The preparation is sensitive to cardiac ion channel blockers: L-type calcium channel blockers, Class-I and Class-III antiarrhythmics change frequency but drugs acting on K ATP channels do not. The assay detects compounds blocking the cardiac rapid delayed-rectifier K channel and is an alternative to the classic "hERG test".Conclusion: hiPSC-CM are a useful in-vitro cardiac model in drug development since they respond appropriately to drugs that modify heart rate in humans.

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“…Between 1994 and 2006, 38 of the new drugs approved by the US Food and Drug Administration (FDA) were later withdrawn from the market because of safety concerns, the majority being cardiotoxic or hepatotoxic [1]. Safety assessments are therefore performed in preclinical drug development for revealing possible drug side effects in particular those that may affect the electrical conduction and beating of the heart [2][3][4][5][6]. Therefore, researchers and pharmaceutical companies have to ensure that the effect of lead candidate compounds on cardiac function strictly satisfy safety criteria.…”

Section: Introductionmentioning

confidence: 99%

Automated multi-parameter measurement of cardiomyocytes dynamics with digital holographic microscopy

Rappaz¹,

Moon²,

Yi³

et al. 2015

Opt. Express

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Abstract:Compounds tested during drug development may have adverse effects on the heart; therefore all new chemical entities have to undergo extensive preclinical assessment for cardiac liability. Conventional intensity-based imaging techniques are not robust enough to provide detailed information for cell structure and the captured images result in lowcontrast, especially to cell with semi-transparent or transparent feature, which would affect the cell analysis. In this paper we show, for the first time, that digital holographic microscopy (DHM) integrated with information processing algorithms automatically provide dynamic quantitative phase profiles of beating cardiomyocytes. We experimentally demonstrate that relevant parameters of cardiomyocytes can be obtained by our automated algorithm based on DHM phase signal analysis and used to characterize the physiological state of resting cardiomyocytes. Our study opens the possibility of automated quantitative analysis of cardiomyocyte dynamics suitable for further drug safety testing and compounds selection as a new paradigm in drug toxicity screens.

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Impedance-Based Detection of Beating Rhythm and Proarrhythmic Effects of Compounds on Stem Cell-Derived Cardiomyocytes

Cited by 90 publications

References 32 publications

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Automated multi-parameter measurement of cardiomyocytes dynamics with digital holographic microscopy

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