Detect therapeutically relevant pathophysiological hypertrophic cardiotoxicity potential of novel therapeutics using Cyprotex’s 3D combined cardiac hypertrophy and multi-parametric high content screening (HCS) cardiotoxicity assay.

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

• Drug-induced cardiovascular toxicity is the leading cause of attrition during drug development. Drugs can exert functional toxicities such as arrhythmia or morphological (structural) damage including changes to the myocardium¹. Evaluation of the potential for both types of cardiotoxicity by novel compounds is essential for the discovery of safe drugs.
• The myocardial tissue comprises only 30% cardiomyocytes, despite this they comprise the majority of the cardiac tissue mass. These terminally differentiated cardiomyocytes can only respond with hypertrophic growth (increased muscle mass) to external stimuli².
• Various stimuli are known to induce cardiac hypertrophy including mechanical and oxidative stress as well as neurohormonal perturbation and metabolic hypoxia². Hypertrophy can be physiologically induced or a pathophysiological response to toxicity.
• Mitochondrial disruption, calcium dyshomeostasis and cellular ATP content have been previously identified as major targets for structural cardiotoxins³ and are used to indicate pathophysiological hypertrophy.
• Three dimensional (3D) high content screening (HCS) allows temporal monitoring of cardiomyocyte spheroid hypertrophy over a 14 day repeat dose period with a terminal measure of mitochondrial function, calcium homeostasis, DNA structure and cellular ATP at day 14.

Utilizing the 3D cardiac combined assay approach all reference compound toxicities were correctly predicted within a 10x C_max cut off. Structural cardiotoxicity was correctly predicted for 94% and pathophysiological hypertrophy potential (PHP) for 81% of the compound set within a 10x C_max cut off.

The combination of an in vitro 3D model that better recapitulates the in vivo cellular physiology of cardiac tissue with multiparametric temporal HCS and a cytotoxicity assay presents a viable screening strategy for the accurate in vivo relevant detection of novel therapeutics that cause structural cardiotoxicity with pathophysiological hypertrophy potential early in drug development.

_{1) Laverty H et al., (2011). How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines? Br J Pharmacol 163(4), 675-693
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3)  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
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) Nam KH et al., (2015) Biomimetic 3D tissue models for advanced high-throughput drug screening. J Lab Autom 20(3); 201-215}