In Vitro Cardiotoxicity

Creative Bioarray provides both standard and novel in vitro drug cardiotoxicity services using iPS cell derived or ES cell derived cardiomyocytes from different species to test and identify cardiotoxic compounds. We offer cardiotoxicity assays such as classical hERG safety assay, QT prolongation assay, arrhythmogenic liability screening, Comprehensive in Vitro Proarrhytmia Assay (CiPA), and customized assays.

With cardiotoxicity being one of the leading causes of safety-related compound attrition and drug withdrawals, cardiac liability remains one of the major hurdles in the drug discovery process. Cardiac arrhythmias, as the most common manifestations of drug-induced cardiotoxicity, are often life-threatening and may result in severe cardiac complications or even sudden death. Therefore, extensive efforts have been put into the development of predictive and reliable assays and technologies to effectively detect possible acute and subtle cardiotoxic effects of test compounds and to minimize both risk and overall cost earlier in the drug development pipeline.

These technologies include:

Microelectrode array (MEA), a high-throughput, functional platform that can be applied to the detection of prolongation, alterations in beat rate, proarrhythmic events, and dysregulation of conduction by measuring the extracellular voltage of beating cardiomyocyte cultures;
High content screening (HCS) that allows simultaneous detection and monitoring of multiple parameters and phenotypes via fluorescent imaging.

Creative Bioarray offers the following in vitro cardiotoxicity assays using MEA and HCS techniques:

•	hERG safety assay The hERG channel, a potassium ion channel encoded by the human ether-à-go-go-related gene, is critical for the cardiac action potential repolarization. Inhibition of hERG function causes lengthening of ventricular action potentials and prolongation of the QT interval. Therefore, evaluating effects of compounds on hERG activity early in drug discovery can greatly reduce the risk of putting extensive efforts in cardiotoxic drugs and prevent them from entering the market.
•	QT prolongation assay The QT interval, a measure of time from the start of the Q wave to the end of the T wave, represents the electrical depolarization and repolarization of the ventricles. QT prolongation implies a delayed ventricular repolarization which may cause ventricular tachyarrhythmias and possibly sudden death. We provide QT prolongation assay to evaluate the cardiotoxicity of compounds with QT interval as the indicator.
•	Arrhythmogenic liability screening By imaging stem cell-derived cardiomyocytes and detecting the action potential of hundreds of individual cells with intracellular Ca2+ transients, drug arrhythmogenic liability can be better evaluated with less false positives and false negatives.
•	*Comprehensive in vitro* proarrhytmia assay (CiPA)** CiPA is a novel cardiac safety screening proposal that evaluates drug effects on each cardiac ion channel type individually (high-throughput), predicts net effect on the cardiomyocyte action potential with computer modeling, and then verifies the in silico conclusions using human stem cell-derived cardiomyocytes. With MEA technology, Creative Bioarray can provide services to detect and analyze effects of candidate compounds on key cardiac ion channels and pathways, with predictive and reproducible data.
•	Calcium transient assay Our calcium transient service offers cardiotoxicity assessment by measuring the calcium release and reuptake from calcium reticulum in iPSC-derived cardiomyocytes. Changes in calcium signal can be detected by treating iPSC-derived cardiomyocytes with a fluorescent calcium-sensitive dye. Calcium transient service allows evaluation of the acute and long-term effects of drugs on electrophysiology of cardiomyocytes.
•	Impedance assay We provide impedance measurements based on these parameters: cardiomyocyte pulsation rate, impedance amplitude and pulsation rate regularity, enabling a real-time detection of cardiotoxicity.
•	Cardiac marker detection Troponin I, a clinically relevant cardiotoxicity biomarker, will be released into the circulatory system by cardiomyocytes after exposure of cardiotoxic compounds. Our Troponin I detecting service is suitable for high throughput screening of cardiotoxic drugs.
•	Customized services Staffed with a group of experienced experts, Creative Bioarray also provides assay development service to meet the special needs of the clients.

Creative Bioarray offers both classic and novel cell culture models for evaluation of cardiotoxicity:

Classic 2D models

iPSC- / ES-derived cardiomyocytes

3D cardiotoxicity assay

With 3D cardiomyocyte spheroids and high-content imaging devices, Creative Bioarray is able to provide a cardiotoxicity service that monitors the effects of compounds on cardiomyocytes at a structural and phenotypic level.

Having gained years of experience, Creative Bioarray is capable of providing considerate and reliable services of high quality for our clients. Our highly experienced experts are ready to support you with their knowledge. If you have any questions or special needs, please contact us for support. We look forward to working with you in the near future.

References

Shinde, Vaibhav, Umesh Chaudhari, Isaia Sotiriadou, Jürgen Hescheler, and Agapios Sachinidis. "In Vitro Methods for Cardiotoxicity Testing." In Vitro Toxicology Systems (2014): 45-77.
Cavero, Icilio, and Henry Holzgrefe. "Comprehensive in vitro Proarrhythmia Assay, a novel in vitro/in silico paradigm to detect ventricular proarrhythmic liability: a visionary 21st century initiative." Expert opinion on drug safety13.6 (2014): 745-758.

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