Abstract
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+].
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