Effect of Ryanodine Receptor Refractoriness on the Induction of Calcium Alternans

Abstract

A numerical model of the rabbit ventricular cardiomyocyte is developed, that properly reproduces calcium alternans at high pacing frequency and experimental postrest-potentiation. We show that calcium alternans may appear due to the alternation in the number of RyR2 ready to open before each beat and not, despite the fact they are present, to oscillations in the SR Ca load. This mechanism is present when activation rates of RyR2 are low and is also favored by a slowing of the RyR2 recovery time from inactivation. Generally, changes in RyR2 refractoriness lead to alternans via two different mechanisms, (the already established) SR Ca2+ load and (a new one) recovery form inactivation. Drugs or mutations which target RyR2 refractoriness should be arrythmogenic via the activation of one of those mechanisms if they decrease the activation or inactivation rate.