Alternans of cardiac calcium cycling in a cluster of ryanodine receptors: a simulation study

Abstract

Mechanical alternans in cardiac muscle is associated with intracellular Ca(2+) alternans. Mechanisms underlying intracellular Ca(2+) alternans are unclear. In previous experimental studies, we produced alternans of systolic Ca(2+) under voltage clamp, either by partially inhibiting the Ca(2+) release mechanism, or by applying small depolarizing pulses. In each case, alternans relied on propagating waves of Ca(2+) release. The aim of this study is to investigate by computer modeling how alternans of systolic Ca(2+) is produced. A mathematical model of a cardiac cell with 75 coupled elements is developed, with each element contains L-type Ca(2+) current, a subspace into which Ca release takes place, a cytoplasmic space, sarcoplasmic reticulum (SR) release channels [ryanodine receptor (RyR)], and uptake sites (SERCA). Interelement coupling is via Ca(2+) diffusion between neighboring subspaces via cytoplasmic spaces and network SR spaces. Small depolarizing 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 Ca(2+) release and sustained through alternation of SR Ca(2+) content. This study provides novel and fundamental insights to understand mechanisms that may underlie intracellular Ca(2+) alternans without the need for refractoriness of L-type Ca or RyR channels under rapid pacing.