Effect of inter-subject variability in determining response to IKr block in human ventricular myocytes

Causes and impact of inter-subject variability in cellular electrophysiological behaviour are unknown. Understanding the effects of this variability is important, particularly as it can modulate response to drug application. Differences between individuals in response to drug action may be due to ionic-level differences, but the effects of these differences may be masked under normal physiological conditions. Therefore, investigating these differences is important to understand the effects of drug action on cells from different individuals. We have developed a methodology to study variability between individuals in cardiac electrophysiology, using populations of models. We performed a simulation study to analyse the response of a population of human ventricular models calibrated using action potential recordings from control experiments, to simulated application of dofetilide, a selective blocker of the delayed rectifier potassium current (IKr). Analysis of the differences between models that developed repolarisation abnormalities and those that did not showed that L-type calcium current conductance was significantly higher and sodium-potassium pump permeability significantly lower in those models that displayed repolarisation abnormalities. Our results show that IKr block can reveal differences in susceptibility to repolarisation abnormalities between cells that appear equally healthy under control conditions.