Automatic Optimization of an in Silico Model of Human iPSC Derived Cardiomyocytes Recapitulating Calcium Handling Abnormalities

Paci, Michelangelo; Pölönen, Risto-Pekka; Cori, Dario; Penttinen, Kirsi; Aalto‐Setälä, Katriina; Severi, Stefano; Hyttinen, Jari

doi:10.3389/fphys.2018.00709

Cited by 67 publications

(125 citation statements)

References 44 publications

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“…A limitation of the Paci2018 hiPS-CM model (15) was noted - namely, failure to reproduce the cessation of the spontaneous electrical activity following strong block of the I NCX , as shown by recent in vitro and in silico experiments (16, 33). A very large window current in Paci2018 for the fast Na + current (I Na ) was identified as the key to sustaining the automaticity upon I NCX block.…”

Section: Methodsmentioning

confidence: 99%

“…To develop the Paci2019 model (details in the Supporting Material): we updated the formulations for I Na and I f with the ones proposed in (16); we optimized the model parameters to fit the same dataset of in vitro AP and CaTr biomarkers used for (15), which have been recorded at 37°C; we validated the model against the same experimental protocols used for (15). …”

Section: Methodsmentioning

confidence: 99%

“…We then test the performance of in silico simulation trials with the populations of models against in vitro drug trials for 5 reference compounds, both in terms of their consistency and to deepen the mechanistic insights unravelled. In detail: i) We present an improved version of the Paci2018 hiPS-CM model (15), providing improved simulation of the Na + /Ca 2+ exchanger (I NCX ) role in sustaining the automaticity of AP. ii) We use high throughput optical measurement of AP, CaTr alone and both to calibrate an in silico population of hiPS-CMs models.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…We also assume that the ratio between RyR channels of type 0 and 1, γ RyR , and the number of Ca 2+ ions that each RyR channel of type 1 can transport, Z, is the same for the different maturity levels. Considering the model (26)- (31), this means that the only adjustment necessary between two maturity levels S 1 and S 2 is an adjustment of the density…”

Section: Definition Of Ca 2+ Fluxesmentioning

confidence: 99%

“…The present report aims to present a number of modifications to improve the accuracy and reliability of these methods. First, using the AP models of O'Hara et al [18], Grandi et al [19], and Paci et al [28,29,30,31] as a basis, we have derived a new AP model to improve representation of experimental data. As our inversion algorithm is based on conducting a huge number of simulations with varying parameter values, it is essential to have a model that is stable with respect to perturbations of the parameters.…”

Section: Introductionmentioning

confidence: 99%

Improved computational identification of drug response using optical measurements of human stem cell derived cardiomyocytes in microphysiological systems

Jæger

Charwat

Charrez

et al. 2019

Preprint

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Cardiomyocytes derived from human induced pluripotent stem cells hold great potential for drug screening applications. However, their usefulness is limited by the relative immaturity of cells' electrophysiological properties as compared to native cardiomyocytes in the adult human heart. In this work, we extend and improve on methodology to address this limitation, building on previously introduced computational procedures which predict drug effects for mature cells based on changes in optical measurements of action potentials and Ca 2+ transients made in stem cell derived cardiac microtissues. This methodology quantifies ion channel changes through the inversion of data into a mathematical model, and maps this response to a mature phenotype through the assumption of functional invariance of fundamental intracellular and membrane channels during maturation.Here we utilize an updated action potential model to represent both immature and mature cells, apply an IC50-based model of dosedependent drug effects, and introduce a continuation-based optimization algorithm for analysis of dose escalation measurements using five 1 drugs with known effects. The improved methodology can identify drug induced changes more efficiently, and quantitate important metrics such as IC50 in line with published values. Consequently, the updated methodology is a step towards employing computational procedures to elucidate drug effects in mature cardiomyocytes for new drugs using stem cell-derived experimental tissues. Flux Description J sl s Flux through the RyRs from the jSR to the SL J n c Flux through the SERCA pumps from the bulk cytosol to the nSR J c d Passive diffusion flux between the dyad and the bulk cytosol J c sl Passive diffusion flux between the SL and the bulk cytosol J s n Passive diffusion flux between the nSR and the jSR J b d Free Ca 2+ binding to a buffer in the dyad J b sl Free Ca 2+ binding to a buffer in the SL J b c Free Ca 2+ binding to a buffer in the bulk cytosol J b s Free Ca 2+ binding to a buffer in the jSR J CaL Ca 2+ -flux through the L-type Ca 2+ channels from the extracellular space to the dyad J bCa Background Ca 2+ flux from the extracellular space to the SL J pCa Ca 2+ flux through the Ca 2+ pump between the extracellular space and the SL J NaCa Ca 2+ flux through the Na + -Ca 2+ exchanger between the extracellular space and the SL J sl e Total Ca 2+ flux from the extracellular space to the SL, defined as J sl e = J bCa + J pCa + J NaCa .

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General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy

Mirams

Yoshinaga

et al. 2019

Clin Pharma and Therapeutics

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This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/ US Food and Drug Administration-sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm.In July 2013, a Think Tank jointly sponsored by Cardiac Safety Research Consortium (CSRC), Health and Environmental Sciences Institute (HESI), and the US Food and Drug Administration (FDA) proposed a new cardiac safety paradigm, Comprehensive in Vitro Proarrhythmia Assay (CiPA). CiPA uses a new mechanistic, model-informed approach to predict the risk of Torsade de Pointes (TdP), a rare but potentially lethal form of ventricular tachycardia that can be induced by drugs and lead to sudden death. 1 Since its inception, global stakeholders including regulatory agencies (the FDA, European Medicines Agency, Health Canada, and the Japan Pharmaceuticals and Medical Devices Agency), industry, and academia have assembled various

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Automatic Optimization of an in Silico Model of Human iPSC Derived Cardiomyocytes Recapitulating Calcium Handling Abnormalities

Cited by 67 publications

References 44 publications

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

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

Improved computational identification of drug response using optical measurements of human stem cell derived cardiomyocytes in microphysiological systems

General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy

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