Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator

Abstract

Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the mechanistic route to TdP is needed. Early afterdepolarisations (EADs) are a cell-level phenomenon in which the membrane of a cardiac cell depolarises a second time before repolarisation, and EADs are seen in hearts during TdP. Therefore, we propose a method of predicting TdP using induced EADs combined with multiple ion channel block in simulations using biophysically-based mathematical models of human ventricular cell electrophysiology. EADs were induced in cardiac action potential models using interventions based on diseases that are known to cause EADs, including: increasing the conduction of the L-type calcium channel, decreasing the conduction of the hERG channel, and shifting the inactivation curve of the fast sodium channel. The threshold of intervention that was required to cause an EAD was used to classify drugs into clinical risk categories. The metric that used L-type calcium induced EADs was the most accurate of the EAD metrics at classifying drugs into the correct risk categories, and increased in accuracy when combined with action potential duration measurements. The EAD metrics were all more accurate than hERG block alone, but not as predictive as simpler measures such as simulated action potential duration. This may be because different routes to EADs represent risk well for different patient subgroups, something that is difficult to assess at present.