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.
Superior cardiac safety studies>
LEAP assay pharmacology with hiPSC-cardiomyoctyes>
Measure changes in propagation patterns and conduction velocity in response to pharmacological compounds>
Structural and functional cardiotoxicity on the same microelectrodes>
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
(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.
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
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.
(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
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.
(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.
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.
All 3 compounds impacted cardiac function by reducing or abolishing spike amplitude, but only pentamidine (hERG trafficking inhibitor) and dox. (chemotherapy agent) induced structural toxicity. Dox. Caused cell death within 24 hours, whereas pentamidine 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.
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