Pathways for cardiotoxicity

Dr Luigi Margiotta-Casaluci was awarded funding to curate published information on cardiotoxicity, caused by blocking L-type calcium channels, to underpin the development and use of non-animal approaches.

Research details

Principal Investigator: Dr Luigi Margiotta-Casaluci
Organisation: Brunel University London
Award type: Strategic grant
Start date: 2017
Duration: 9 months
Amount: £30k

Case study

Over the last decade there has been considerable interest from industry and regulatory bodies in the wider use of non-animal approaches to investigate how chemicals, including pharmaceuticals, interact with biological processes and biochemical pathways to help predict whether they will be harmful to humans and/or the environment. The concept of the adverse outcome pathway (AOP) has been developed to support this by providing a framework to organise information into a description of the critical steps that occur from the initial chemical interaction (referred to as the molecular initiating event) through to molecular, cellular and tissue events that ultimately lead to adverse effects at the organ and organism-level.

In the short-term AOPs can be used to help design bespoke mechanistic in vitro and in silico models for specific toxicological endpoints and to identify knowledge gaps which need to be addressed – together supporting the long-term goal of replacing animal use in safety testing. Because of their potential benefits, the OECD has provided guidance and infrastructure to encourage the development and use of AOPs – standardising the language used and outlining a process for review and endorsement. To date, nine AOPs have been published by the OECD, including AOPs for neurological and reproductive adverse events.

3Rs benefits (actual and potential)

During this nine-month project, Luigi developed the first AOPs for cardiotoxicity. These form a mini-network of AOPs that describe three different mechanisms by which the blockade of L-type calcium channels can lead to adverse effects, including heart failure. The AOPs were developed by identifying, critiquing and collating information from over 150 primary publications on the effects of calcium channel blockers on different parts of the cardiovascular system, and publications examining the effects of genetic manipulations on different components of the L-type calcium channel. The AOPs have been published on the AOPWiki to allow peer review as part of the process towards OECD endorsement.

Scientific and technological benefits

Luigi curated over 1,100 in vitro, ex vivo and in vivo data points relevant to blockade of L-type calcium channels into a database. The database includes quantitative pharmacokinetic and pharmacodynamic data that can be used to inform and interpret in silico and in vitro models, for example, dose response data for each drug/endpoint, exposure duration and quantification method. An innovative approach to graphically represent the strength of evidence supporting each key event relationship in the AOP was also developed by Luigi. This could be applied to other AOPs to help highlight knowledge gaps and assess the completeness of the AOP as part of the endorsement process.

Added value

Luigi has presented the AOPs at five conferences and workshops, including the Safety Pharmacology Society 2018 Annual Meeting where he was awarded a Junior Investigator Award. As a result of the expertise developed with the NC3Rs award, Luigi is a member of a €6.7M Horizon 2020 GOLIATH consortium where he will guide the development of an AOP network for chemicalinduced metabolic disruption.

This case study was published in our 2019 Research Review.