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

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 sarcoplasmic reticulum is strong. 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 Ca 2+ 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. alternans, saddle-node bifurcation 1. Intoduction Cardiac arrhythmias constitute a leading public health problem and cause most cases of sudden cardiac death. In the US alone, sudden cardiac death accounts for approximately 300, 000 − 450, 000 lives every year [1]. Among the many forms of cardiac arrhythmias, cardiac alternans feature prominently. This 5 rhythm disturbance at the level of a single cardiac myocyte is characterised by alternating patterns of the membrane potential and the intracellular calcium (Ca 2+ ) concentration on successive beats. For instance, at one beat, a long action potential duration (APD) is accompanied by a large intracellular Ca 2+ transient, while on the next beat, the APD is shortened concomitant with a 10 small amplitude Ca 2+ transient. As a consequence, contractile efficiency is impaired, which in turn can cause a detrimental reduction in blood flow. In early experimental studies, the intracellular Ca 2+ concentration was averaged across a cardiac myocyte. The advent of high-resolution microscopy revealed that alternating Ca 2+ dynamics were already present at individual Ca 2+ release units 15 (CRU). While one CRU follows a pattern of large-small-large Ca 2+ transients, neighbouring CRUs exhibit small-large-small Ca 2+ transients. Crucially, both CRUs experience the same membrane potential. These findings gave rise to the concept of subcellular Ca 2+ alternans [2-10] and illustrated that nonlinear processes govern cardiac dynamics across multiple scales: the cell wide membrane 20 potential and the Ca 2+ fluxes restricted to single dyadic clefts.The existence of subcellular Ca 2+ alternans reinforces the n...

A master stability function approach to cardiac alternans

“…Since the computation of the MSF rests on the PWL nature of the CRU model, it is worth asking how well this approximation describes the dynamics of the full nonlinear model. As shown in Lai et al (2019), the PWL model captures the core dynamics of the nonlinear model very well. Of course, there are parameter regimes of the nonlinear model that cannot be captured with the current parametrisation of the PWL model used here.…”