Calcium Alternans in a Couplon Network Model of Ventricular Myocytes: Roles of Sarcoplasmic Reticulum Load

Abstract

Intracellular calcium (Ca) alternans of cardiac myocytes has been shown in many experimental studies, and the mechanisms remain incompletely understood. We recently developed a “3R theory” in which alternans arises as a result of the interactions of three critical properties: Randomness of Ca sparks; Recruitment of a Ca spark to its neighboring Ca release units (CRUs); and Refractoriness of the CRU. On the other hand, experimental studies have shown that sarcoplasmic reticulum (SR) Ca load plays important roles in the genesis of Ca alternans. In this study, we use computer simulation to study how SR Ca load and other physiological parameters, such as RyR sensitivity, SERCA pump, CRU spacing, Na-Ca exchange strength, L-type Ca conductance, etc., affect Ca alternans. Our model consists of 100 x 20 x 10 CRUs coupled via Ca diffusion in the cytoplasmic and SR space. Each CRU contains 100 RyRs with individual RyRs simulated stochastically. We developed a method to calculate the primary spark rate and the recruitment rate, and paced the model to periodically to elicit Ca alternans. We show that altering the physiological parameters not only directly change the 3 R's but also alters the SR Ca load (or the total Ca of the cell), and thus Ca alternans properties. However, higher SR Ca load causes more Ca leak which in turn causes RyRs to be more sensitive to cytosolic Ca, affecting primary spark rate and recruitment. Therefore, our present study shows that although the 3R theory does not include the SR load per se, the SR Ca load affects Ca alternans via its effects on the 3 R's.