Development of an AOP for cardiotoxicity mediated by the blockade of L-type calcium channel

Calcium ions play a vital role in cellular and organism physiology. These ions are a central component of a complex system of intracellular messengers that mediates a wide range of biological processes. 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.

• 2019 Research Review: Pathways for cardiotoxicity