Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C017

Oral Communications

Inward rectifier current downregulation in heart failure promotes triggered activity in a novel model of rat ventricular electrophysiology and calcium handling

H. J. Stevenson-Cocks1, M. A. Colman1, E. White1, A. P. Benson1

1. University of Leeds, Leeds, United Kingdom.


Aberrant intracellular calcium (Ca2+) handling contributes to both the mechanical and electrical dysfunction seen in heart failure, promoting arrhythmogenesis and potentially resulting in sudden cardiac death. The underlying mechanisms for these processes, occurring across different temporal and spatial scales, can be difficult to dissect with experimental techniques, however computational modelling approaches can provide quantitative and mechanistic insight in their place. Previous experimental data from our laboratory (1) has shown that inward rectifier (IK1) channel expression is reduced by 55% in failing rat myocytes compared to control (p = 0.01, two-way ANOVA; n = 12) and spontaneous Ca2+ release is increased, yet we have been unable to use existing computational models of rat ventricular electrophysiology to explore this pro-arrhythmic behaviour as they are unable to reproduce sub-cellular spatio-temporal Ca2+ handling dynamics. Thus, we have been unable to explore the hypothesis that this more frequent release may result from increased sarcoplasmic reticulum (SR) load combined with decreased membrane stability. A new computational model was therefore developed by integrating a recent rat ventricular electrophysiology model (2) with a novel model of stochastic spatio-temporal Ca2+ handling dynamics developed in our laboratory (3). The newly-developed model was used to dissect and quantify changes in Ca2+ homeostasis caused by remodelling of key ion channels. A 50% reduction in IK1 (comparable to that observed experimentally) resulted in a 57% increase in action potential duration (APD) in our simulations, from 58.1 to 91.4 ms. This prolonged APD resulted in greater loading of the SR, raising [Ca2+]SR to super-threshold levels and giving rise to more frequent spontaneous release events. These, in turn, triggered forward-mode (depolarising) sodium-calcium exchange (INaCa), leading to triggered action potentials; a pro-arrhythmic phenomenon. Resting membrane potential was also depolarised by 3.3 mV in HF myocytes in our simulations, thus a smaller Ca2+ release (ergo, a smaller concomitant INaCa current) was required to elicit triggered activity. The newly-developed model has reproduced experimental findings from the laboratory and provided insight into the mechanisms of spontaneous Ca2+ release in HF; that a reduced repolarising IK1 current prolongs APD sufficiently for [Ca2+]SR to exceed the threshold for spontaneous release, promoting spontaneous activity and providing a trigger for arrhythmia development in failing myocytes. Thus, the model provides a supplementary and stand-alone research tool to explore how sub-cellular changes in electrophysiology and Ca2+ handling result in arrhythmias at the tissue- and organ-levels.

Where applicable, experiments conform with Society ethical requirements