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1 Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, United Kingdom
2 Unit of Cardiac Physiology, School of Medicine, The University of Manchester, Manchester, United Kingdom
3 Royal (Dick) Vet School, University of Edinburgh, Edinburgh, United Kingdom
4 Physics, The University of Manchester, Manchester, United Kingdom
* To whom correspondence should be addressed. E-mail: henggui.zhang{at}manchester.ac.uk.
Mechanical alternans in cardiac muscle is associated with intracellular Ca2+ alternans. Mechanisms underlying intracellular Ca2+ alternans are unclear. In previous experimental studies we produced alternans of systolic Ca2+ under voltage clamp either by partially inhibiting the Ca2+ release mechanism or by applying small depolarising pulses. In each case alternans relied on propagating waves of Ca2+ release. The aim of this study is to investigate by computer modelling how alternans of systolic Ca2+ is produced. A mathematical model of a cardiac cell with 75 coupled elements is developed, each element contains L-type Ca2+ current, a subspace into which Ca release takes place, a cytoplasmic space, sarcoplasmic reticulum (SR) release channels (RyR) and uptake sites (SERCA). Inter-element coupling is via Ca2+ diffusion between neighbouring subspaces via cytoplasmic spaces and network SR spaces. Small depolarising pulses were simulated by step changes of cell membrane potential (20 mV) with random block of L-type channels. Partial inhibition of the release mechanism is mimicked by applying a reduction of RyR open probability in response to full stimulation by L type channels. In both cases systolic alternans follow consistent with our experimental observations, being generated by propagating waves of Ca2+ release and sustained through alternation of SR Ca2+ content. This study provides novel and fundamental insights to understand mechanisms that may underlie intracellular Ca2+ alternans without the need for refractoriness of L-type Ca or RyR channels under rapid pacing.
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