Ca2+ Alternans in a Cardiac Myocyte Model that Uses Moment Equations to Represent Heterogeneous Junctional SR Ca2+

摘要

Multiscale whole-cell models that accurately represent local control of Ca²⁺-induced Ca²⁺ release in cardiac myocytes can reproduce high-gain Ca²⁺ release that is graded with changes in membrane potential. Using a recently introduced formalism that represents heterogeneous local Ca²⁺ using moment equations, we present a model of cardiac myocyte Ca²⁺ cycling that exhibits alternating sarcoplasmic reticulum (SR) Ca²⁺ release when periodically stimulated by depolarizing voltage pulses. The model predicts that the distribution of junctional SR [Ca²⁺] across a large population of Ca²⁺ release units is distinct on alternating cycles. Load-release and release-uptake functions computed from this model give insight into how Ca²⁺ fluxes and stimulation frequency combine to determine the presence or absence of Ca²⁺ alternans. Our results show that the conditions for the onset of Ca²⁺ alternans cannot be explained solely by the steepness of the load-release function, but that changes in the release-uptake process also play an important role. We analyze the effect of the junctional SR refilling time constant on Ca²⁺ alternans and conclude that physiologically realistic models of defective Ca²⁺ cycling must represent the dynamics of heterogeneous junctional SR [Ca²⁺] without assuming rapid equilibration of junctional and network SR [Ca²⁺].