Dynamic Action Potential Clamp Investigation of Pro-Arrhythmic Risk of Drugs Binding to hERG Potassium Channels

Abstract

Many commonly used drugs can bind to and block the hERG channel and cause the potentially life threatening acquired long-QT syndrome.Whilst obtaining an IC50 for drug block of hERG is relatively straight forward, this is a poor surrogate for risk of pro-arrhythmia. Predicting the overall consequences of hERG drug block on cardiac electrical activity is complicated by the fact that the effect of hERG channel block varies in different cells (e.g. epicardial, mid-myocardial, endocardial, Purkinje) of the heart. Furthermore it is significantly altered by the electrical remodeling that occurs in many chronic heart conditions. With the aging of our population and an increasing proportion of people with chronic heart conditions it is especially important to understand how disease states affect the consequences of hERG drug block and risk of pro-arrhythmia.Here we describe a recently developed dynamic action potential clamp system (dAPC) to investigate the effect of hERG block on cardiomyocytes. The system consists of conventional whole cell voltage clamp study of ion channels in mammalian expression systems, coupled to a real time computer model of human cardiomyocyte action. The dAPC system integrates the current recordings from a patch clamped cell into an in-silico cell model, the output of which is then used to determine the voltage of the patch clamped cell. When used in combination with a state of the art drug perfusion system this integrative approach will permit testing of drugs on specified ion channels in a physiologically relevant environment, something that is not possible with conventional patch clamp methods.