Video image-based analysis of single human induced pluripotent stem cell derived cardiomyocyte beating dynamics using digital image correlation

Ahola, Antti; Kiviaho, Anna; Larsson, Kim; Honkanen, Markus; Aalto‐Setälä, Katriina; Hyttinen, Jari

doi:10.1186/1475-925x-13-39

Cited by 79 publications

(92 citation statements)

References 23 publications

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“…The symptomatic 41-year old patient had experienced seizures, episodes of unconsciousness and syncope before β-blocker (bisoprolol) medication. The healthy control human iPS cells were derived from skin fibroblasts of a healthy 55-year old female (QTc interval, 406 ms) [44]. …”

Section: Methodsmentioning

confidence: 99%

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The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes

Kuusela

Kim

Räsänen

et al. 2016

Stem Cell Rev and Rep

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Healthy human heart rate fluctuates overtime showing long-range fractal correlations. In contrast, various cardiac diseases and normal aging show the breakdown of fractal complexity. Recently, it was shown that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) intrinsically exhibit fractal behavior as in humans. Here, we investigated the fractal complexity of hiPSC-derived long QT-cardiomyocytes (LQT-CMs). We recorded extracellular field potentials from hiPSC-CMs at baseline and under the effect of various compounds including β-blocker bisoprolol, ML277, a specific and potent IKs current activator, as well as JNJ303, a specific IKs blocker. From the peak-to-peak-intervals, we determined the long-range fractal correlations by using detrended fluctuation analysis. Electrophysiologically, the baseline corrected field potential durations (cFPDs) were more prolonged in LQT-CMs than in wildtype (WT)-CMs. Bisoprolol did not have significant effects to the cFPD in any CMs. ML277 shortened cFPD in a dose-dependent fashion by 11 % and 5–11 % in WT- and LQT-CMs, respectively. JNJ303 prolonged cFPD in a dose-dependent fashion by 22 % and 7–13 % in WT- and LQT-CMs, respectively. At baseline, all CMs showed fractal correlations as determined by short-term scaling exponent α. However, in all CMs, the α was increased when pharmacological compounds were applied indicating of breakdown of fractal complexity. These findings suggest that the intrinsic mechanisms contributing to the fractal complexity are not altered in LQT-CMs. The modulation of IKs channel and β1-adrenoreceptors by pharmacological compounds may affect the fractal complexity of the hiPSC-CMs.Electronic supplementary materialThe online version of this article (doi:10.1007/s12015-016-9686-0) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

“…All the hiPSC lines (UTA.04602.WT, UTA.00208.LQT1, UTA.00211.LQT1, UTA.00303.LQT1 and UTA.00313.LQT1) and the differentiated CMs from them have been previously characterized elsewhere [41, 43, 44]. …”

Section: Methodsmentioning

confidence: 99%

The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes

Kuusela

Kim

Räsänen

et al. 2016

Stem Cell Rev and Rep

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“…Calcium and contraction-measurement systems have been leveraged for cardiotoxicity testing (26). Ahola et al (27, 28) developed a video-based contact-free method to quantify the biomechanics of beating hiPS-CMs, by processing simultaneous recording of motion and Ca 2+ transients (CaTr) from fluorescence videos. However, AP signals represent key aspects of cardiotoxicity responses that may not be captured by field potentials, CaTr or mechanical contractions.…”

Section: Introductionmentioning

confidence: 99%

All-optical electrophysiology refines populations of in silico human iPS-CMs for drug evaluation

Paci

Passini

Klimas

et al. 2019

Preprint

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12High-throughput in vitro drug assays have been impacted by recent advances in human induced 13 pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) technology and by contact-free all-14 optical systems simultaneously measuring action potential (AP) and Ca 2+ transient (CaTr). 15 Parallel computational advances have shown that in silico models can predict drug effects with 16 high accuracy. In this work, we combine these in vitro and in silico technologies and 17 demonstrate the utility of high-throughput experimental data to refine in silico hiPS-CM 18 populations, and to predict and explain drug action mechanisms. Optically-obtained hiPS-CM 19 AP and CaTr were used from spontaneous activity and under pacing in control and drug 20 conditions at multiple doses. 21 An updated version of the Paci2018 model was developed to refine the description of hiPS-22 CM spontaneous electrical activity; a population of in silico hiPS-CMs was constructed and 23 calibrated using the optically-recorded AP and CaTr. We tested five drugs (astemizole, 24 dofetilide, ibutilide, bepridil and diltiazem), and compared simulations against in vitro optical 25 recordings. 26 Our simulations showed that physiologically-accurate population of models can be obtained 27 by integrating AP and CaTr control records. Thus constructed population of models predicted 28 correctly the drug effects and occurrence of adverse episodes, even though the population was 29 optimized only based on control data and in vitro drug testing data were not deployed during 30 its calibration. Furthermore, the in silico investigation yielded mechanistic insights, e.g. 31through simulations, bepridil's more pro-arrhythmic action in adult cardiomyocytes compared 32 to hiPS-CMs could be traced to the different expression of ion currents in the two. 33Therefore, our work: i) supports the utility of all-optical electrophysiology in providing high-34 content data to refine experimentally-calibrated populations of in silico hiPS-CMs, ii) offers 35 insights into certain limitations when translating results obtained in hiPS-CMs to humans and 36 iii) shows the strength of combining high-throughput in vitro and population in silico 37 approaches. 38 39 3 Significance 40We demonstrate the integration of human in silico drug trials and optically-recorded 41 simultaneous action potential and calcium transient data from human induced pluripotent stem 42 cell-derived cardiomyocytes (hiPS-CMs) for prediction and mechanistic investigations of drug 43 action. We propose a population of in silico models i) based on a new hiPS-CM model 44 recapitulating the mechanisms underlying hiPS-CM automaticity and ii) calibrated with all-45 optical measurements. We used our in silico population to predict and evaluate the effects of 5 46 drugs and the underlying biophysical mechanisms, obtaining results in agreement with our 47 experiments and one independent dataset. This work supports the use of high-content, high-48 quality all-optical electrophysiology data to develop, calibrate ...

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“…Video microscopy-based motion field imaging analysis is able to characterize motion-derived contractile properties of cardiomyocytes (Ahola et al, 2014;Hayakawa et al, 2014;Maddah et al, 2015) in a non-invasive manner. Motion field imaging has been demonstrated to detect acute (<1 h) druginduced effects of cardiac ion channel drugs in hiPS-CMs (Hayakawa et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Chronic drug‐induced effects on contractile motion properties and cardiac biomarkers in human induced pluripotent stem cell‐derived cardiomyocytes

Kopljar

Bondt

Vinken

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEIn the pharmaceutical industry risk assessments of chronic cardiac safety liabilities are mostly performed during late stages of preclinical drug development using in vivo animal models. Here, we explored the potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to detect chronic cardiac risks such as drug-induced cardiomyocyte toxicity. EXPERIMENTAL APPROACHVideo microscopy-based motion field imaging was applied to evaluate the chronic effect (over 72 h) of cardiotoxic drugs on the contractile motion of hiPS-CMs. In parallel, the release of cardiac troponin I (cTnI), heart fatty acid binding protein (FABP3) and N-terminal pro-brain natriuretic peptide (NT-proBNP) was analysed from cell medium, and transcriptional profiling of hiPS-CMs was done at the end of the experiment. KEY RESULTSDifferent cardiotoxic drugs altered the contractile motion properties of hiPS-CMs together with increasing the release of cardiac biomarkers. FABP3 and cTnI were shown to be potential surrogates to predict cardiotoxicity in hiPS-CMs, whereas NT-proBNP seemed to be a less valuable biomarker. Furthermore, drug-induced cardiotoxicity produced by chronic exposure of hiPS-CMs to arsenic trioxide, doxorubicin or panobinostat was associated with different profiles of changes in contractile parameters, biomarker release and transcriptional expression. CONCLUSION AND IMPLICATIONSWe have shown that a parallel assessment of motion field imaging-derived contractile properties, release of biomarkers and transcriptional changes can detect diverse mechanisms of chronic drug-induced cardiac liabilities in hiPS-CMs. Hence, hiPS-CMs could potentially improve and accelerate cardiovascular de-risking of compounds at earlier stages of drug discovery.

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Video image-based analysis of single human induced pluripotent stem cell derived cardiomyocyte beating dynamics using digital image correlation

Cited by 79 publications

References 23 publications

The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes

The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes

All-optical electrophysiology refines populations of in silico human iPS-CMs for drug evaluation

Chronic drug‐induced effects on contractile motion properties and cardiac biomarkers in human induced pluripotent stem cell‐derived cardiomyocytes

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