Effect of RyR2 refractoriness and hypercalcemia on calcium overload, spontaneous release, and calcium alternans

In this work we use a computer model of a ventricular\nrabbit myocyte to study several factors that affect sarcoplasmic\nreticulum (SR) calcium load, such as hypercalcemia,\nSR calcium buffering, or ryanodine receptor (RyR2)\ndynamics. General conditions for the appearance of calcium\nspontaneous release in situations with calcium overload\nare obtained. Furthermore, we study the appearance\nof alternans under these conditions. The presence of calcium\nalternans may be due to either a steep calcium load\nrelease relation, resulting in oscillations in SR Ca content,\nor to a slow recovery from refractoriness of the RyR2. We\nfind that a change in calsequestrin buffering dynamics or\nextracellular calcium concentration greatly affects the appearance\nof the former type of alternans, but not of the\nlatter.