Cross - site comparison of excitation-contraction coupling using impedance and field potential recordings in hiPSC cardiomyocytes

Bot, Corina; Juhász, Krisztina; Haeusermann, Fabian; Polonchuk, Liudmila; Traebert, Martin; Stoelzle-Feix, Sonja

doi:10.1016/j.vascn.2018.06.006

Cited by 35 publications

(20 citation statements)

References 36 publications

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“…Using CiPA as an example, the approach proposed was to identify proarrhythmic risk based on several key modalities including: (1) assessment of several major ion channels in transfected cell lines; (2) in silico modeling of the ion channel effects; (3) proarrhythmic assessment in hiPSC-CMs; and (4) clinical assessment of electrocardiograms from phase I human studies. Data that emerged from CiPA show that optical- and multielectrode array-based platforms using commercially sourced hiPSC-CMs enable an 87% accuracy in predicting proarrhythmic liability across geographically diverse testing laboratories ( Blinova et al , 2018 ), with similar studies being reported by others ( Bot et al , 2018 ).…”

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confidence: 67%

Blinded, Multicenter Evaluation of Drug-induced Changes in Contractility Using Human-induced Pluripotent Stem Cell-derived Cardiomyocytes

Saleem

Meer

Katili

et al. 2020

Toxicological Sciences

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Abstract Animal models are 78% accurate in determining whether drugs will alter contractility of the human heart. To evaluate the suitability of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for predictive safety pharmacology, we quantified changes in contractility, voltage, and/or Ca2+ handling in 2D monolayers or 3D engineered heart tissues (EHTs). Protocols were unified via a drug training set, allowing subsequent blinded multicenter evaluation of drugs with known positive, negative, or neutral inotropic effects. Accuracy ranged from 44% to 85% across the platform-cell configurations, indicating the need to refine test conditions. This was achieved by adopting approaches to reduce signal-to-noise ratio, reduce spontaneous beat rate to ≤ 1 Hz or enable chronic testing, improving accuracy to 85% for monolayers and 93% for EHTs. Contraction amplitude was a good predictor of negative inotropes across all the platform-cell configurations and of positive inotropes in the 3D EHTs. Although contraction- and relaxation-time provided confirmatory readouts forpositive inotropes in 3D EHTs, these parameters typically served as the primary source of predictivity in 2D. The reliance of these “secondary” parameters to inotropy in the 2D systems was not automatically intuitive and may be a quirk of hiPSC-CMs, hence require adaptations in interpreting the data from this model system. Of the platform-cell configurations, responses in EHTs aligned most closely to the free therapeutic plasma concentration. This study adds to the notion that hiPSC-CMs could add value to drug safety evaluation.

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confidence: 67%

Blinded, Multicenter Evaluation of Drug-induced Changes in Contractility Using Human-induced Pluripotent Stem Cell-derived Cardiomyocytes

Saleem

Meer

Katili

et al. 2020

Toxicological Sciences

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“…In short, the CMs start beating regularly and synchronized approximately 48 h after thawing/seeding and they display normal action potential profiles. Furthermore, they have been shown to have an expected electrophysiological response to different drugs (Higa et al, 2016;Da Rocha et al, 2017;Bot et al, 2018;Stillitano et al, 2017). Electrophysiological studies performed on iPS-CMs derived from patients with familial hypertrophic cardiomyopathy show that the patient-specific CMs have more irregular action potentials and increased irregular contractility compared to control-CMs (Han et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Cardiac hypertrophy in a dish: A human stem cell based model

et al. 2020

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Cardiac hypertrophy is an important and independent risk factor for the development of heart failure. To better understand the mechanisms and regulatory pathways involved in cardiac hypertrophy, there is a need for improved in vitro models. In this study, we investigated how hypertrophic stimulation affected human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). The cells were stimulated with endothelin-1 (ET-1) for 8, 24, 48, 72, or 96h. Parameters including cell size, ANP-, proBNP-, and lactate concentration were analyzed. Moreover, transcriptional profiling using RNA-sequencing was performed to identify differentially expressed genes following ET-1 stimulation. The results show that the CMs increase in size by approximately 13% when exposed to ET-1 in parallel to increases in ANP and proBNP protein and mRNA levels. Furthermore, the lactate concentration in the media was increased indicating that the CMs consume more glucose, a hallmark of cardiac hypertrophy. Using RNA-seq, a hypertrophic gene expression pattern was also observed in the stimulated CMs. Taken together, these results show that hiPSC-derived CMs stimulated with ET-1 display a hypertrophic response. The results from this study also provide new molecular insights about the underlying mechanisms of cardiac hypertrophy and may help accelerate the development of new drugs against this condition.

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“…( 2018 ) investigated human stem cell-derived CMs provided by four different suppliers in three different platforms on multiple sites and saw differences with FPDc ranging from 271–577 ms. Comparison of four commercial cardiomyocyte lines in another study confirmed differences at baseline level with FPD ranging from 246–548 ms, highlighting the need for rate control during drug screening ( Bot et al., 2018 ).…”

Section: Introductionmentioning

confidence: 90%

Comparison of 10 Control hPSC Lines for Drug Screening in an Engineered Heart Tissue Format

et al. 2020

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Summary Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are commercially available, and cardiac differentiation established routine. Systematic evaluation of several control hiPSC-CM is lacking. We investigated 10 different control hiPSC-CM lines and analyzed function and suitability for drug screening. Five commercial and 5 academic hPSC-CM lines were casted in engineered heart tissue (EHT) format. Spontaneous and stimulated EHT contractions were analyzed, and 7 inotropic indicator compounds investigated on 8 cell lines. Baseline contractile force, kinetics, and rate varied widely among the different lines (e.g., relaxation time range: 118-471 ms). In contrast, the qualitative correctness of responses to BayK-8644, nifedipine, EMD-57033, isoprenaline, and digoxin in terms of force and kinetics varied only between 80% and 93%. Large baseline differences between control cell lines support the request for isogenic controls in disease modeling. Variability appears less relevant for drug screening but needs to be considered, arguing for studies with more than one line.

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Cross - site comparison of excitation-contraction coupling using impedance and field potential recordings in hiPSC cardiomyocytes

Cited by 35 publications

References 36 publications

Blinded, Multicenter Evaluation of Drug-induced Changes in Contractility Using Human-induced Pluripotent Stem Cell-derived Cardiomyocytes

Blinded, Multicenter Evaluation of Drug-induced Changes in Contractility Using Human-induced Pluripotent Stem Cell-derived Cardiomyocytes

Cardiac hypertrophy in a dish: A human stem cell based model

Comparison of 10 Control hPSC Lines for Drug Screening in an Engineered Heart Tissue Format

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