Identifying drug response by combining measurements of the membrane potential, the cytosolic calcium concentration, and the extracellular potential in microphysiological systems

Jæger, Karoline Horgmo; Wall, Sam; Charwat, Verena; Healy, Kevin E.; Tveito, Aslak

doi:10.1101/2020.05.29.122747

Cited by 2 publications

(2 citation statements)

References 40 publications

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“…21,29 The design aligns cells immediately upon loading, fostering rapid production of native cardiac ECM, and alignment of the cells' contractile machinery fostering geometrically aligned contraction. The cardiac MPS model has been validated in a number of both experimental and computational studies 21,[30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

“…The design aligns cells immediately upon loading, fostering rapid production of native cardiac extracellular matrix (ECM), and alignment of the cells’ contractile machinery fostering geometrically aligned contraction. The cardiac MPS model has been validated in a number of both experimental and computational studies 21,25,29‐31 . By assaying hiPSC‐CMs expressing a genetically encoded calcium sensor (GcAMP6f), loaded with a voltage‐sensitive fluorescent probe (BeRST), we assessed the electrophysiology and calcium handling of the heart muscle during serial drug exposures.…”

Section: Introductionmentioning

confidence: 99%

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In vitro safety “clinical trial” of the cardiac liability of drug polytherapy

Charrez

Charwat

Siemons

et al. 2021

Clinical Translational Sci

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Only a handful of FDA Emergency Use Authorizations exist for drug and biologic therapeutics that treat SARS-CoV-2 infection. Potential therapeutics include repurposed drugs, some with cardiac liabilities. We report on a chronic preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with repurposed hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock Phase I safety clinical trial. The MPS contained human heart muscle derived from induced pluripotent stem cells. The effect of drug response was measured using outputs that correlate with clinical measurements such as QT interval (action potential duration) and drug-biomarker pairing. Chronic exposure (10 days) of heart muscle to HCQ alone elicited early afterdepolarizations and increased QT interval past 5 days. AZM alone elicited an increase in QT interval from day 7 onwards, and arrhythmias were observed at days 8 and 10.Monotherapy results mimicked clinical trial outcomes. Upon chronic exposure to HCQ and AZM polytherapy, we observed an increase in QT interval on days 4-8. Interestingly, a decrease in arrhythmias and instabilities was observed in polytherapy relative to monotherapy, in concordance with published clinical trials. Biomarkers, most of them measurable in patients' serum, were identified for negative effects of monotherapy or polytherapy on tissue contractile function, morphology, and antioxidant protection. The cardiac MPS correctly predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities. This high content system can help clinicians design their trials, rapidly project cardiac outcomes, and define new monitoring biomarkers to accelerate access of patients to safe COVID-19 therapeutics.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In vitro safety “clinical trial” of the cardiac liability of drug polytherapy

Charrez

Charwat

Siemons

et al. 2021

Clinical Translational Sci

Self Cite

View full text Add to dashboard Cite

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Model-driven optimal experimental design for calibrating cardiac electrophysiology models

Lei

Clerx

Gavaghan

et al. 2022

Preprint

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Models of the cardiomyocyte action potential (AP) have contributed immensely to the understanding of heart function, pathophysiology, and the origin of heart rhythm disturbances. However, AP models are nonlinear, complex, and can contain more than a hundred differential equations, making them difficult to parameterise. Therefore, cellular cardiac models have been limited to describing `average cell' dynamics, when cell-specific models would be ideal to uncover inter-cell variability but are too experimentally challenging to be achieved. Here, we focus on automatically designing experimental protocols that allow us to better identify cell-specific maximum conductance values for each major current type—optimal experimental designs—for both voltage-clamp and current-clamp experiments. We show that optimal designs are able to perform better than many of the existing experiment designs in the literature in terms of identifying model parameters and hence model predictive power. For cardiac cellular electrophysiology, this approach will allow researchers to define their hypothesis of the dynamics of the system and automatically design experimental protocols that will result in theoretically optimal designs.

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Identifying drug response by combining measurements of the membrane potential, the cytosolic calcium concentration, and the extracellular potential in microphysiological systems

Cited by 2 publications

References 40 publications

In vitro safety “clinical trial” of the cardiac liability of drug polytherapy

In vitro safety “clinical trial” of the cardiac liability of drug polytherapy

Model-driven optimal experimental design for calibrating cardiac electrophysiology models

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