Cardiovascular safety pharmacology: beyond arrhythmic risk assessment

Cardiovascular safety pharmacology arose from the need to assess certain forms of drug induced functional cardiotoxicity in toxicology within a regulatory framework. Cardiotoxic effects resulting from direct or indirect pharmacological effects are difficult to apprehend in conventional toxicology studies, whether electrophysiological and/or hemodynamic. The reflex regulatory systems of the cardiovascular system, and in particular the autonomic nervous system, interfere with and very often minimize the functional impact of these pharmacological effects, which are sometimes only visible over a very short time window. Modeling approaches now make it possible to assess key hemodynamic parameters, going beyond blood pressure alone. Non-clinical cardiovascular safety pharmacology must continue to evolve toward a comprehensive framework for arrhythmic risk, in order to improve its translational relevance to humans and better bridge non-clinical QT prolongation data with clinical risk assessment. It also needs to integrate concepts from clinical research, such as Coumel's triangle, autonomic conflict or hidden cardiotoxicity. The ultimate goal of cardiovascular safety pharmacology should extend beyond protecting participants in clinical trials. It should broaden its scope to include patient subpopulations with underlying cardiovascular disease, who are often the most vulnerable to functional cardiotoxic effects. Twenty-five years after their initial publication, the safety pharmacology guidelines are currently undergoing revision. This review aims to foster a more balanced and comprehensive approach to cardiovascular safety pharmacology, beyond arrhythmic risk.