Formation of Subcellular Calcium Waves in Cardiac Myocytes: Characterizing Timescales via Mathematical Modeling

Abstract

Subcellular Calcium (Ca) cycling plays fundamental roles in normal heart dynamics. In cardiac myocytes, the elementary Ca cycling events are Ca sparks: random discretized Ca release events due to random and collective openings of the ryanodine receptor (RyR) channels clustered in Ca release units (CRUs). A typical cardiac myocyte includes about 10,000 to 20,000 CRUs, and the spatial arrangement of CRUs varies widely across myocyte type and changes in diseased conditions. Dysfunction of the CRU network leaves cells prone to subcellular Ca waves, notorious triggers of highly arrhythmogenic delayed afterdepolarizations. Recent experimental studies have isolated three timescales involved in the formation of Ca waves: rate of sarcoplasmic reticulum (SR) Ca reuptake, intrinsic RyR refractoriness, and a so-called “idle” period. Here we use a physiologically detailed computational model of a spatial and stochastic CRU network to study the variables that contribute to the aforementioned timescales, and identify how the relative dominance of each affects the morphology of Ca waves. We show that the “idle” period is far from idle, as it emerges out of complex Ca mediated CRU-to-CRU interactions in both the myoplasm and SR. We also find that while reduced refractory period and increased SR Ca diffusion enhance the local initiation of waves, they hinder propagation, resulting in fractionated wave events. Furthermore, at very short refractory periods the system degenerates into spiral waves and chaos. Pinpointing the mechanisms underlying the variety of observed wave morphologies is an important step in our understanding of diseased states, as each may play a different role in arrhythmogenesis.