Latency to the Onset of Calcium Waves in Cardiac Myocytes is Predicted by Criticality Theory

Abstract

Spontaneous calcium (Ca) waves must emerge near-synchronously in thousands of contiguous myocytes to produce delayed afterdepolarizations (DADs) in cardiac tissue. Previous studies have shown as Ca load increases, the time to onset of a spontaneous Ca wave after pacing (latency), as well as its variability, decreases. Two proposed mechanisms include the time period required to refill the sarcoplasmic reticulum (SR) Ca stores and regain Ca release channel excitability, and the latter plus an “idle period.” Here we used patch-clamped Fluo-4-loaded isolated rabbit ventricular myocytes to detect Ca waves and DADs following pacing trains. Longer pacing trains enhancing Ca loading decreased latency and its variability. Using paced premature beats, latency outlasted the period required for SR refilling and Ca release channel recovery, consistent with an additional “idle period.” From combined experimental data, simulations, and theoretical analysis, we present evidence that the “idle period” can be explained by criticality theory (Biophys J 2012;11:2433), related to the probability that a cluster of Ca release units large enough to initiate a Ca wave will self-organize. This theory directly accounts for the observed shortening of latency and its variability as Ca load increases.