Inward Rectifier Current Downregulation Promotes Spontaneous Calcium Release in a Novel Model of Rat Ventricular Electrophysiology

Aberrant intracellular calcium handling, as observed in diseases such as heart failure, promotes lethal ventricular arrhythmias and sudden cardiac death. Recent data from our laboratory suggests that reduced expression of the inward rectifier current in failing rat myocytes increases spontaneous calcium release, however existing computational models are unable to reproduce the underlying stochastic calcium cycling dynamics and so we have been unable to use simulation approaches to explore the cause of this pro-arrhythmic behaviour. Here, we develop a novel model of rat ventricular electrophysiology that reproduces normal spatio-temporal calcium dynamics. Simulations implementing a similar reduction in inward rectifier current to that observed experimentally show that spontaneous calcium release is promoted by action potential prolongation and sarcoplasmic reticulum loading in the presence of a depolarised resting membrane potential. Combined, these effects can result in triggered activity. The model therefore provides insight into arrhythmogenic mechanisms in failing ventricular myocytes and can be utilised to further explore pro-arrhythmic behaviour caused by abnormal calcium handling.