Calcium ions play a vital role in cellular and organism physiology. A diverse set of calcium channels contribute to the timely regulation of calcium currents at cellular level. Among them, the L-type calcium channel is responsible for the excitation-contraction coupling of skeletal, smooth, and cardiac muscle. Pharmaceuticals that unintentionally block this channel in cardiac cells may impair heart function and health, leading to various cardiac pathologies and predisposing individuals to heart failure. Advancing our understanding of the mechanisms underlying those adverse effects is of paramount importance if we want to develop effective strategies able to accurately predict potential cardiotoxicity as early as possible during drug development. The aim of this project is to develop an Adverse Outcome Pathway (AOP) that describes the series of causally related key events triggered by the blockade of L-type calcium channel, and that can ultimately lead to heart failure. This AOP will represent a valuable knowledge base able to guide the identification of key events that are highly predictive of in vivo toxicity, and that can be measured in vitro without relying on animal testing. The knowledge base will also be used as platform to drive future development projects aimed at incorporating additional layers of complexity in the model, and at driving the transition towards a fully quantitative AOP able to effectively support decision-making.

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Outputs

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The main results of the work have been presented at various national and international meetings. A publicly available copy of the presentation is available here. More peer-reviewed publications will follow.  

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• (2019) Development of an adverse outcome pathway (AOP) for cardiotoxicity mediated by the blockade of L-type calcium channels. Margiotta-Casaluci, L.; Dusza, H.; Moreira, I.; Winter, M.J.; Prior, H. Journal of Pharmacological and Toxicological Methods, 99 (2019), Article 106595.

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• AOP 261: https://aopwiki.org/aops/261

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• AOP 262: https://aopwiki.org/aops/262

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Impact

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• The output of this project has been considered as one of 12 case studies in the NC3Rs Research Review 2019, showcasing key NC3Rs-funded research carried out in the last 5 years. Being selected as one of the 12 case study has been a great honour and achievement, as it highlights both the impact and the high quality of our research. The NC3Rs Research Review 2019 can be downloaded from this link. 

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• In 2018, Dr Margiotta-Casaluci was thrilled to receive the Junior Investigator Award of the Society of Safety Pharmacology (SPS). Thanks to the Award, he was able to present his work on cardiotoxicity at the annual meeting in Washinghton DC. 

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