The Timing Statistics of Spontaneous Calcium Release in Cardiac Myocytes

Mesfin Asfaw,Yohannes Shiferaw,Enric Alvarez-Lacalle

doi:10.1371/journal.pone.0062967

Mesfin Asfaw, Yohannes Shiferaw + Show 1 more

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https://doi.org/10.1371/journal.pone.0062967

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Abstract

A variety of cardiac arrhythmias are initiated by a focal excitation that disrupts the regular beating of the heart. In some cases it is known that these excitations are due to calcium (Ca) release from the sarcoplasmic reticulum (SR) via propagating subcellular Ca waves. However, it is not understood what are the physiological factors that determine the timing of these excitations at both the subcellular and tissue level. In this paper we apply analytic and numerical approaches to determine the timing statistics of spontaneous Ca release (SCR) in a simplified model of a cardiac myocyte. In particular, we compute the mean first passage time (MFPT) to SCR, in the case where SCR is initiated by spontaneous Ca sparks, and demonstrate that this quantity exhibits either an algebraic or exponential dependence on system parameters. Based on this analysis we identify the necessary requirements so that SCR occurs on a time scale comparable to the cardiac cycle. Finally, we study how SCR is synchronized across many cells in cardiac tissue, and identify a quantitative measure that determines the relative timing of SCR in an ensemble of cells. Using this approach we identify the physiological conditions so that cell-to-cell variations in the timing of SCR is small compared to the typical duration of an SCR event. We argue further that under these conditions inward currents due to SCR can summate and generate arrhythmogenic triggered excitations in cardiac tissue.

Highlights

It is generally believed that sudden cardiac death is induced by a focal excitation that can propagate and form wave break and reentry [1,2,3,4,5]
Statistics of a single Ca release units (CRUs) we explore in detail the factors that determine the timing statistics of spontaneous Ca sparks at a single CRU with N Ryanodine Receptor (RyR) channels
In this paper we have studied the timing statistics of spontaneous Ca sparks at the single CRU, cell, and tissue level

Summary

Introduction

It is generally believed that sudden cardiac death is induced by a focal excitation that can propagate and form wave break and reentry [1,2,3,4,5]. The underlying mechanism and the properties of these focal excitations are not well understood It is not known what are the factors that determine when a focal excitation will occur in a region of cardiac tissue. In general we expect a focal excitation to be potentially dangerous if it occurs during the diastolic interval (DI) when cardiac tissue is excitable. In this period cardiac tissue can sustain electrical wave propagation which can form wave break by collisions with the wave back of the previous beat, or at anatomical obstacles in the tissue [6]

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