Introducing Drug Action into Single-Cell Cardiac Models

Abstract

Drug development failures due to adverse cardiac effects cost the drugs industry millions of dollars every year. Many of these failures may be predicted through mathematical modelling of drug actions. In order to achieve this it is necessary to investigate the effectiveness of different ways of incorporating drug action into models. Five different single-cell cardiac models are studied with and without drug action. These comprise two rabbit models (Mahajan et al., 2008; Shannon et al., 2004) and three other species (ten Tusscher and Panfilov, 2006; Hinch et al., 2004; Faber et al., 2007). The L-type calcium channel regulation properties of the different models are compared, and their calcium-dependent and voltage-dependent inactivation properties are considered. It is found that the different models respond in very different ways to the introduction of drug action through a simple pore block with none of the models successfully reproducing experimental results for both drugs that are considered. It is therefore concluded that the kinetics of drug action on active and inactive channels must be included to better model the drug action. The differing responses of the models at different pacing frequencies and drug doses indicate that it is necessary to perform experiments at a range of frequencies and drug concentrations.