Proceedings of The Physiological Society

Future Physiology (Leeds, UK) (2017) Proc Physiol Soc 39, PC58

Poster Communications

Mechanisms of arrhythmia triggers in heart failure predicted by a novel model of rat ventricular electrophysiology

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

1. University of Leeds, Leeds, United Kingdom.

Aberrations in intracellular calcium (Ca2+) handling, particularly in diseases such as heart failure (HF), are known to increase vulnerability to lethal arrhythmias, potentially resulting in sudden cardiac death. The underlying mechanisms for these processes can be difficult to explore experimentally, but computational modelling approaches can provide quantitative and mechanistic insight into such complex pathophysiological phenomena. Though previous experimental data from our laboratory1 has shown that expression of the Kir2.1 (IK1) channel is reduced by 55% in HF myocytes compared to control (p = 0.01, two-way ANOVA; n = 12) and spontaneous Ca2+ release is increased, current computational models of rat ventricular electrophysiology are unable to capture many aspects of healthy and, by extension, diseased Ca2+ handling (such as high-frequency restitution properties), so we have been unable to support or explore the hypothesis that this more frequent release may result from increased sarcoplasmic reticulum (SR) Ca2+ loading combined with decreased membrane stability. A new model was therefore developed by combining a recent model2 of rat ventricular electrophysiology with a novel model3 of stochastic spatio-temporal Ca2+ handling dynamics developed in our laboratory. The newly-developed model was used to dissect and quantify the electrophysiological changes associated with remodelling of key ion channels and Ca2+ homeostasis in HF that promote arrhythmogenic behaviour. A similar reduction (50%) to that observed experimentally in the IK1 current resulted in an 85% increase in action potential duration (APD) in a simulation study, from 49 to 91 ms. This prolonged APD allowed increased time for SR loading, leading to raised levels of [Ca2+]SR and more frequent spontaneous release events. These, in turn, triggered forward-mode (depolarising) Na+-Ca2+ exchanger activity, leading to increased occurrences of triggered action potentials. Resting membrane potential was also depolarised by 2.71 mV in HF myocytes in the model, allowing a smaller spontaneous release of [Ca2+]SR (and a concomitantly reduced inward Na+-Ca2+ exchanger current) to elicit a triggered action potential. The newly-developed model has reproduced experimental results from the laboratory and provided insight into the underlying mechanisms of spontaneous release in HF myocytes; that a reduced repolarising IK1 current prolongs APD and allows more time for SR loading, promoting spontaneous Ca2+ release events. Combined with a destabilised membrane, this provides a trigger for arrhythmia development in failing myocytes. Thus, the model provides a supplementary and stand-alone research tool, which can be used to explore how sub-cellular changes associated with HF may result in arrhythmias at the tissue- and organ-levels.

Where applicable, experiments conform with Society ethical requirements