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

• Published in: Communications in nonlinear science & numerical simulation 2020-06, Vol.85, p.105181, Article 105181
• Main Authors: Lai, Yi Ming, Coombes, Stephen, Thul, Rüdiger
• Format: Article
• Language: English
• Subjects: Alternations; Buffers; Calcium; Calcium cycling; Calcium ions; Cardiomyocytes; Channels; Computer simulation; Deactivation; Diffusion; Filaments; Luminal diffusion; Membranes; Modulators; Numerical analysis; Saddle-node bifurcation; Sarcoplasmic reticulum; Subcellular calcium alternans; Synchrony; Toolkits
• ISSN: 1007-5704; 1878-7274
• DOI: 10.1016/j.cnsns.2020.105181

•Calcium diffusion in the sarcoplasmic reticulum critically changes cardiac alternans.•L-type calcium channels and calcium buffers modulate calcium alternans nonintuitively.•Single channel current interacts nonlinearly with calcium-dependent inactivation.•Buffers can promote and abolish subcellular calcium alternans. 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.