Self-Organization of Pacemaking Sites for Calcium Waves and Oscillations in Cardiac Myocytes

Abstract

Calcium (Ca) sparks are elementary events of intracellular Ca signaling, which tend to occur randomly. Ca waves and whole-cell Ca oscillations occur under Ca overload and disease conditions. How Ca waves emerge from Ca sparks is not completely understood. We developed a three-dimensional model for Ca cycling which contains 100x20x10=20,000 identical Ca release units (CRUs), simulating the CRU network corresponding to a complete cardiac myocyte with dimensions of 100x20x10 micrometers. Using this model, we can generate the well known Ca signaling hierarchy: Ca quarks, Ca sparks, macro-sparks, abortive waves, and full Ca waves. We can also induce spiral waves within the cell, a wave phenomenon widely observed in myocyte experiments. Besides the well known experimental observation that increasing Ca loading promotes these wave dynamics, we also make the following observations: 1) The diffusion rate of Ca is a key parameter. Spontaneous Ca waves occur only when the diffusion rate is above a critical value. 2) When the model is homogeneous, Ca waves originate from different locations via a self-organizing process. This self-organizing process is influenced by, but does not require, heterogeneity. 3) When the model contains heterogeneities, such as heterogeneous Ca release channel distribution, Ca waves can originate from different locations or occur repeatedly from the same location. In real cardiac rabbit ventricular myocytes loaded with Fluo-4 AM to image intracellular Ca, Ca waves typically originate from different locations after successive rapid pacing episodes. In conclusion, our results indicate that Ca waves in cardiac myocytes originate predominantly as a result of self-organizing processes rather than pre-existing heterogeneities.