Cardiotoxicity and Safety

Cardiotoxicity traces
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Cardiotoxicity refers to the dysfunction or damage to the heart caused by exposure to natural or synthetic substances. The inability to predict the cardiovascular liability of therapeutic compounds prior to clinical trials has resulted in numerous costly late-stage drug development failures and market withdrawals.

The Maestro Pro and Edge microelectrode array (MEA) systems are uniquely suited to evaluate in vitro cardiotoxicity. With sensitive measurements of the electrical, contractile, and conduction activity of cardiomyocytes in culture, the Maestro MEA platform is a vital tool to inform any cardiac safety testing paradigm.

LEAP assay pharmacology with hiPSC-cardiomyoctyes

The Maestro Pro and Edge’s local extracellular action potential (LEAP) assay noninvasively measures cardiac action potential morphology and easily detects early afterdepolarizations (EADs). Now more subtle alterations to action potential morphology like triangulation can be quantified. Action potential morphology changes measured with LEAP are consistent with previous reports of labor-intensive traditional methods like manual patch clamp.

E-4031 first prolonged repolarization and then generated repolarization irregularities in cardiomyocytes in cardiotoxicity
E-4031 at APD30 from cardiomyocytes in cardiotox assay
E-4031 APD90 measurements in cardiotoxicity assay for CiPA
Duration of the LEAP signal in a dose-dependent manner from hiPSC-CMs
Shortened the duration of the LEAP signal in a dose-dependent manner.
APD90 from LEAP signal from cardiomyocytes in toxicity assay
Triangulation of LEAP signal at higher concentrations, consistent with patch clamp results.
ADP30 results from LEAP recordings with cardiomyocytes

(B) E-4031 first prolonged repolarization and then generated repolarization irregularities. (C) Duration of the LEAP signal was shortened in a dose-dependent manner. (D) Triangulation was induced at higher concentrations, consistent with patch clamp results


Superior cardiac safety studies


The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative aims to update the existing cardiac safety testing paradigms to better evaluate arrhythmogenic risk of new compounds.  In the CiPA pilot study, six core sites used the Maestro for their MEA studies with two different cell types and eight compounds with known mechanisms. The Maestro and accompanying software tools demonstrated high reliability across replicates, sites, and cell types, while accurately measuring changes in depolarization (spike amplitude), repolarization (field potential duration), and detecting arrhythmias

Field potential recordings from cardiomyocytes with drug dosing
Cardiotoxicity study results showing field potential change from cardiomyocytes
Evaluation of carditoxocity in cardiomyocytes and recording of field potential duration with concentration
Analysis for arrhythmias in cardiomyocytes
Change in amplitude against concentration in cardiomyocyte cytotoxicity assay
hiPSC-cardiomyocytes amplitude change with drug assay concentration

(A) CiPA pilot study results for three representative compounds across six Maestro sites using Axiogenesis Cor.4U (orange) or CDI iCell (blue) hiPSC-cardiomyocytes (hiPSC-CMs). Example raw field potential waveforms (inset) are presented before (black) and after (orange or blue) dosing. The Maestro reliably detected field potential duration (FPD) prolongation for hERG K+ blockers, FPD reduction for Ca2+ blockers, and spike amplitude reduction for Na+ blockers across sites and cell types.


CiPA Pilot Study Results showed that the Maestro MEA was the most reliable and most accurate with the lowest variability


In the multi-site, blinded CiPA Pilot Study, the CiPA team demonstrated the utility of hiPSC-cardiomyocytes to detect cardioactive compounds. We are proud that the Maestro MEA system played a pivotal role in the study. Nice work Maestro MEA users.


Download CiPA Pilot Study Paper




The follow-up CiPA Myocyte Phase II validation study expanded its predecessor's scope to test 28 drugs from low, intermediate, and high torsades de pointes (TdP) risk categories at 11 sites around the globe. In this study the CiPA team demonstrated the utility of hiPSC-CMs to detect drug-induced arrhythmogenic effects. We are proud that the Maestro MEA system played a pivotal role in the study. More importantly, we are thankful for all the Maestro MEA users at big pharma for making us look great.


Download CiPA Phase II Study Paper


Measure changes in propagation patterns and conduction velocity in response to pharmacological compounds

In an hiPSC-CM syncytium, beating is generally initiated in one portion of the culture (pacer region) and propagates like a wave through the tissue. Pharmacological agents and cardiac disorders can affect conduction by 1) modifying the excitability of the cells, or 2) altering the gap junction coupling between cells.


The baseline conduction velocity plot of hiPSC-CM
Conduction velocity comparison with different doses of cardiotoxicity assay
Conduction velocity of hiPSC-CMs
The propagation consistency was more variable and greatly decreased after the dosing compared to baseline

(E) When a Na+ channel blocker, was added to a hiPSC-CM network, a decrease in conduction velocity was observed. (F) Addition of a treatment to hiPSC-CMs caused a disruption in propagation pattern, and thus a decrease in propagation consistency from beat to beat.


Structural and functional cardiotoxicity on the same microelectrodes

Cardiotoxicity can be both functional and structural. Expand your MEA assay by measuring cell coverage and viability from the same microelectrodes used to cardiomyocyte electromechanical function. Because impedance is non-invasive and label-free, MEA Viability can be repeated many times to capture both acute and chronic cytotoxicity.

Learn more about MEA Viability.

Cardiotoxicity Functional Activity from cardiomyoctyes with MEA Viability
Cardiotoxicity Structural Activity from cardiomyoctyes with MEA Viability

All 3 compounds impacted cardiac function by reducing or abolishing spike amplitude, but only penta (hERG trafficking inhibitor) and dox. (chemotherapy agent) induced structural toxicity. Dox. Caused cell death within 24 hours, whereas penta caused cell death over the course of 6 days.

In the maps below, brighter colors indicate higher spike amplitudes (left) or higher cell coverage (right); darker colors indicate lower spike amplitudes or cell death.


All products and application data are for research use only and not intended for human diagnostic or therapeutic uses

Application Note: Development of a functional cardiotoxicity assay for evaluating the safety of cell therapies
CAR T App Note: Development of a functional cardiotoxicity assay for evaluating the safety of cell therapies


In this app note you will learn how:

>> HER2-targeted CAR T cells kill iPSC-derived cardiomyocytes in vitro

>> Non-transduced T cells show no toxicity toward iPSC-CMs, and HER2-CAR T cells do not kill iPSC-derived neurons

>> HER2-CAR T induce electrophysiological changes in iPSC-CMs, often before changes in viability are observed

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Assay Steps
CiPA Cardiotox assay protocol steps

Getting started with Maestro Pro and Edge couldn't be easier. Culture your cells in an Axion multiwell MEA plate (Day 0).  Load the MEA plate into the Maestro MEA system at the desired recording times and begin recording. Analyze the cardiomyocyte activity in the MEA plate label-free and in real-time with AxIS Navigator Cardiac Module software.  Add test compounds as required (e.g. Day 7).

Learn how to add MEA Viability to your protocol

Read the Protocol