Calcium buffers and L-type calcium channels as modulators of cardiac subcellular alternans

Yi Ming Lai,Stephen Coombes,Rüdiger Thul

doi:10.1016/j.cnsns.2020.105181

Yi Ming Lai, Stephen Coombes + Show 1 more

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https://doi.org/10.1016/j.cnsns.2020.105181

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Abstract

In cardiac myocytes, calcium cycling links the dynamics of the membrane potential to the activation of the contractile filaments. Perturbations of the calcium signalling toolkit have been demonstrated to disrupt this connection and lead to numerous pathologies including cardiac alternans. This rhythm disturbance is characterised by alternations in the membrane potential and the intracellular calcium concentration, which in turn can lead to sudden cardiac death. In the present computational study, we make further inroads into understanding this severe condition by investigating the impact of calcium buffers and L-type calcium channels on the formation of subcellular calcium alternans when calcium diffusion in the cytosol is weak and the main route of Ca2+ transport in the myocyte is via the sarcoplasmic reticulum. Through numerical simulations of a two dimensional network of calcium release units, we show that increasing calcium entry is proarrhythmogenic and that this is modulated by the calcium-dependent inactivation of the L-type calcium channel. We also find that while calcium buffers can exert a stabilising force and abolish subcellular Ca2+ alternans, they can significantly shape the spatial patterning of subcellular calcium alternans. Taken together, our results demonstrate that subcellular calcium alternans can emerge via various routes and that calcium diffusion in the sarcoplasmic reticulum critically determines their spatial patterns.

Highlights

IntroductionCalcium cycling links the dynamics of the membrane potential to the activation of the contractile filaments
In cardiac myocytes, calcium cycling links the dynamics of the membrane potential to the activation of the contractile filaments
As this study focuses on subcellular Ca2+ alternans in two-dimensional Ca2+ release units (CRU) networks, we wish to visualise the Ca2+ concentration simultaneously across the 100 two spatial dimensions and time

Summary

Introduction

Calcium cycling links the dynamics of the membrane potential to the activation of the contractile filaments. Perturbations of the calcium signalling toolkit have been demonstrated to disrupt this connection and lead to numerous pathologies including cardiac alternans This rhythm disturbance is characterised by alternations in the membrane potential and the intracellular calcium concentration, which in turn can lead to sudden cardiac death. Among the 5 many forms of cardiac arrhythmias, cardiac alternans feature prominently This rhythm disturbance at the level of a single cardiac myocyte is characterised by alternating patterns of the membrane potential and the intracellular calcium (Ca2+) concentration on successive beats. Each CRU can be conceptualised as a network of interacting components such as L-type Ca2+ channels, sodium-calcium 25 exchangers (NCXs) and ryanodine receptors (RyRs) These local networks are coupled via Ca2+ diffusion through both the cytosol and the sarcoplasmic reticulum (SR). In addition to the findings in [14], we observed subcellular

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