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Multiparametric Functional & Structural Cardiac Safety Analysis

Assess both functional and structural toxicity of your compounds in fully functional and validated hiPSC-derived cardiomyocytes. Ncardia’s Multiparametric cardiac safety analysis provides a multiparametric analysis to investigate potential cardiotoxicity of test compounds over a relatively long time span. This full service contains an electrophysiological assay (acute), impedance analysis (contractility) and biomarker release (structural).

What are your benefits?

Multiparametric analysis
Acute and long-term analysis, assessing functional and structural toxicity

Reproducible results
Use of fully validated and quality-controlled cardiomyocytes

Clinically relevant biomarker
Troponin I is the key biomarker for detecting myocardial damage in patients

 

Introduction

As complex mechanisms underlie drug-induced toxicity, some compound effects will only become evident after longer incubation times. For that reason, our Multiparametric Safety Assay enables a long term analysis after compound addition. Efficient cardiac safety assessment should analyse structural as well as functional toxicity.

This multiparametric approach allows functional toxicity analysis by a combination of electrophysiology and impedance monitoring of hiPSC-derived cardiomyocytes. The structural toxicity is defined by the detection of Troponin I (a clinically relevant and established diagnostic marker for myocardial damage) release after compound addition. The Multiparametric Safety Assay provides the most comprehensive readout that generates mechanism-specific cardiotoxicity profiles, and reduces the risk of missing any cardiotoxic effect of candidate drugs.

Workflow

Case Study

Simultaneous Measurement of Contractility, Electrophysiology, and Troponin I Secretion to Determine Cardiotoxicity of anti-cancer drugs.

Many novel oncology therapeutics may induce cardiotoxicity by inhibiting survival pathways which are shared by both tumors and cardiac cells. As complex mechanisms underlie drug-induced toxicity, some compound effects will only become evident after longer incubation times. Multiplexing impedance and MEA with cTnI release assay allows for a simultaneous assessment of short-term and long-term as well as structural and functional drug-induced cardiotoxicity from a single well.

Case study specifications:

Cell type

Pluricyte® Cardiomyocytes

Format

48 wells
Technology xCelligence CardioECR (ACEA)

Assay window

Acute (30 min) till long-term (64h) effect

Assay controls

0.1% DMSO (vehicle control)

Test compounds

Nilotinib, lapatinib, doxorubicin, and ponatinib

Compound concentrations

10 µM, 3 µM, 0.3 µM

Parameters

Electrophysiology: beat rate, beat rate CoV, field potential duration, depolarization peak amplitude, proarrhythmic events

Contractility: impedance amplitude (Cell Index) and peak width

Troponin I release

 

Results

Unlike lapatinib and nilotinib, ponatinib and doxorubicin caused a concentration- and time-dependent increase in cTnI release (right panels, represented as counts, dashed line indicates baseline cTnI levels), which correlated with reduced Cell Index (CI) values (left panels). The CI can also be affected by changes in the morphology or contractility of the cardiomyocyte monolayer as seen after addition of nitrendipine. Therefore, the CI could not be used as a direct measurement for structural cardiotoxicity.

Multiplexing impedance and MEA with cTnI release assay for simultaneous assessment of short-term and long-term as well as structural and functional drug-induced cardiotoxicity.

Conclusion

Whereas addition of nilotinib and lapatinib caused a (functional) contractile/electrophysiological deficit, doxorubicin exhibited a long-term toxic effect in both MEA and impedance measurements. While lapatinib and nilotinib did not cause structural toxicity as measured by cTnI release, ponatinib and doxorubicin induced a dose- and time-dependent increase in cTnI release which correlated with reduced cell index values.

Interested?

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