Cardiotox Screen: Cardiac Safety Liability Assessment

Our novel Cardiotox Screen assay utilizes a combination of cellular assays comprising multi-parameter phenotypic profiling techniques to assess both the functional and structural cardiotoxicity potential of novel compounds from a single plate based assay.

Cyprotex delivers consistent, high quality data with the flexibility to adapt protocols based on specific customer requirements.


Background information:
  • Cardiotoxicity is a major cause of drug attrition during preclinical and clinical drug development1.
  • Drugs can exhibit functional changes defined as an acute alteration in the mechanical function of the myocardium or structural in nature as defined by morphological damage to cardiomyocytes and/or loss of viability.
  • In recent years in vitro strategies have been developed to allow the high throughput assessment of functional cardiomyocyte changes through fast kinetic monitoring of calcium transients, while structural morphology can be monitored in a high throughput manner using high content imaging (HCI) combined with biochemical intracellular ATP assessment.
  • Pointon et al., 2013 highlighted calcium homeostasis, mitochondrial function and ATP content as key endpoints for the in vitro detection of structural cardiotoxicity2.
  • Functional cardiotoxins can alter contraction frequency (chronotrophy), force (inotropy) or pattern (arrhythmia) creating disturbances in calcium transient patterns within contracting cardiomyocytes.
  • Fast kinetic fluorescent reading of cardiomyocyte calcium transients has been shown to detect atypical patterns and changes in cell-beating rate caused by hERG, Ca2+ and Na+ channel blockers3.
  • Cardiotoxins can also indirectly affect expression of ion channels, which alongside morphological changes require a longer period of compound exposure.
  • Our novel Cardiotox Screen panel assesses both structural and functional cardiotoxicity endpoints from a single cell population by utilising our proprietary software to detect and analyze individual calcium transients alongside high content image analysis of cellular morphology and biochemical cytotoxicity assessment.
  • The full Cardiotox Screen panel comprises acute and pretreated (24h) exposure periods to capture cardiotoxins with time-dependent effects and is used in the assessment of cardiac safety liability in drug discovery.


Cardiotox Screen Protocol


Data from Cyprotex's Cardiotox Screen


1) Sirenko O et al. (2012) Multiparameter in vitro assessment of compound effects on cardiomyocyte physiology using iPSC cells. J Biomol Screen 18(1): 39-53
2) Pointon A et al (2013) Phenotypic profiling of structural cardiotoxins in vitro reveals dependency on multiple mechanisms of toxicity. Toxicol Sci 132(2): 317-326
3) Laverty HG et al. (2011) How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines? Br J Pharmacol 163(4): 675-693
4) Cross MJ et al. (2015) Physiological, pharmacological and toxicological considerations of drug-induced structural cardiac injury. Br J Pharmacol 172(4): 957-974
5) Ravenscroft S et al. (2016) Cardiac non-myocyte cells show enhanced pharmacological function suggestive of contractile maturity in stem cell derived cardiomyocyte microtissues. Toxicol Sci 152(1): 99-112


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Paul Walker

Paul Walker, PhD

VP Head of Toxicology & Innovation Efficiency

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Cyprotex enables and enhances the prediction of human exposure, clinical efficacy and toxicological outcome of a drug or chemical. By combining quality data from robust in vitro methods with contemporary in silico technology, we add value, context and relevance to the ADME-Tox data supplied to our partners in the pharmaceutical or chemical industries.