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Cardiac safety assessment using the Maestro MEA system

Ncardia's expertise in MEA assays enables detailed electrophysiological detection of potential test compounds, in a broad throughput range. For this application note, we assessed the effects of cardioactive compounds on the electrophysiology of our Pluricyte Cardiomyocytes using the Maestro MEA system.

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Application note

Assessment methods

The Pluricyte Cardiomyocytes were cultured on Maestro Classic MEA 48 plate in Pluricyte Cardiomyocyte Medium for 9 days. A set of pro-arrhythmic drugs was dissolved in DMSO at a concentration of 10mM and then diluted in 10-fold serial dilutions. The cardiomyocytes were then treated with this set of pre-diluted pro-arrhythmic drugs in a cumulative dose response experiment. Acute-drug effects were directly measured using the Axion Maestro MEA system. The data were analyzed to determine the compound effects on beat period, field potential duration, and spike amplitude.

Results

Calcium channel blockers affect the plateau phase between the depolarization and repolarization phase, resulting in a shortening of the field potential duration. As shown in this graph, L-type calcium channel blockers nifedipine (left) and diltiazem (right) shorten the field potential duration of the cardiomyocytes in a concentration-dependent manner.

hERG potassium channel blockers block the rapid component of the delayed rectifier outward potassium current (IKr), thereby delaying the repolarization phase. This results in an increase in field potential duration and flattening of the repolarization peak. At higher concentrations, blocking of the hERG channel may lead to TdP-like arrhythmias. This figure shows this prolongation of the field potential duration (FPD) of Pluricyte Cardiomyocytes induced by hERG potassium channel blockers E4031 and dofetilide. Furthermore, TdP-like arrhythmias were frequently observed at high concentrations of E4031 and dofetilide.

Sodium channel blockers affect the depolarization phase of the field potential by blocking sodium channels (INa), resulting in a decrease in sodium spike amplitude. This figure shows that sodium channel blocker mexiletine indeed decreases the sodium spike amplitude in the cardiomyocytes in a concentration-dependent manner. Mexiletine also blocks hERG (IKr) potassium channels, shown here by an increase in field potential duration.

 

Isoproterenol is a β-adrenergic receptor agonist; activation of this receptor results in an increased beat rate (decreased beat period) and consequently a reduction in field potential duration. Isoproterenol was found to have a concentration-dependent effect on the beat rate of the cardiomyocytes, as well as on the absolute field potential duration.

Conclusion

This application note shows how we study the cardiac safety profile of compounds at an early stage of drug development, using the Maestro MEA system.

Through our >10 years of expertise, our MEA assay services can support your Drug Discovery projects, providing you with detailed analyses of either patient derived or genetically modified iPSC models, to study your required disease phenotype and its response to compounds. Results are highly relevant for studying cardiac safety or efficacy profile of compounds through several stages of your drug development projects.

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