Simulating the Effects of Polyunsaturated Fatty Acids on Human Slowly Activating Delayed Rectifier Potassium Channel (KCNQ1 - KCNE1)

Abstract

The consumption of omega-3 polyunsaturated fatty acids (PUFA) from fish oil is recommended to prevent arrhythmias and reduce risk of sudden cardiac death. PUFA modulate activity of various cardiac ion channels. The models of electrical activity of the heart based on mathematical formulation are a part of the efforts to improve the understanding and prediction of heart behaviour. The ion channels gating models are a basic part of models of cardiac electrical activity. The human slowly activated delayed rectifier potassium channel (IKs) is a key contributor to ventricle repolarization. The goal of this study is to determine the effects of PUFA on IKs. Further it aims to predict the effects of PUFA induced alteration in IKs on the ventricular action potential (AP). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were used to perform the experiments. The Markov chain formulation of ion channel models constitutes an important improvement and is able to adequately describe the kinetic behaviour of the channel. The IKs Markovian model involves 17 conformation states and 15 parameters. This model was used to simulate the data obtained from voltage clamp experiment. The parameters of the model were identified using Nelder-Mead simplex method. The main results are the following. Acute exposure to PUFA increased IKs and augment the time constant. The Chronic exposure reduced IKs. Incorporating the identified model to human ventricle cell model caused AP prolongation in the Chronic case. The Acute EPA exposure caused AP shortening. The Acute DHA had no significant effect to AP in ten Tusscher et al. model and caused AP shortening in O'Hara et al. model. The Grandi et al. model was insensitive to IKs modifications. In conclusion the underlying mechanism of PUFA is very complex. Effects on the IKs and AP is may have proarrhythmic as well as antiarrhythmic consequences. Thus, the advice to increase the intake of PUFA should be adjusted with respect to pathophysiological setting of individual patient.