Mathematical modeling demonstrated that increased IP3R2 expression in heart failure calcium release units increases calcium spark fidelity and facilitates pro-arrhythmic multi-spark events.
Mathematical modeling suggests that increased IP3R2 expression in heart failure may contribute to pro-arrhythmic Ca2+ signaling via increased spark frequency, while simultaneously serving a compensatory function by countering changes in spark morphology due to RyR2 remodeling.
Ryanodine receptors (RyR) and IP 3 receptors (IP 3 R) are Ca 2+ release channels expressed on the endoplasmic/sarcoplasmic reticulum (ER/SR) membrane in various cell types. Both the spatial localization and the distinct gating properties of these channels contribute to the diverse cellular functions controlled by intracellular Ca 2+ signaling. It is known that both RyR2s and IP 3 R2s are expressed on the SR membrane of ventricular cardiomyocytes and that the expression of IP 3 R2s on the SR is increased in cardiac diseases such as heart failure (HF), and evidence that Ca 2+ release through IP 3 R2s can influence RyR2-mediated Ca 2+ release in excitation-contraction coupling has been described. However, despite the suggested functional role for crosstalk between RyR2s and IP 3 R2s, especially under pathologic conditions, most previous mathematical models of cardiomyocyte Ca 2+ signaling have accounted for only RyR2s in isolation. We hypothesized that the combined effects of (1) fragmentation and dispersion of RyR2s within calcium release units (CRUs) and (2) increased expression of IP 3 R2s that occur in HF promote pro-arrhythmic Ca 2+ spark behavior, which may contribute to increased risk of arrhythmogenic Ca 2+ wave formation and incidence of ventricular arrhythmias. We built a stochastic mathematical model of local SR Ca 2+ release events—Ca 2+ sparks—that incorporates both RyR2s and IP 3 R2s. This model considers the spatial arrangement of RyR2s and IP 3 R2s relative to one another based on published immunohistochemistry studies and the arrangement of RyR2s under HF and healthy control conditions based on super-resolution microscopy data. RyR2 and IP 3 R2 gating are modeled based on single channel patch clamp studies which show that (1) RyR2 gating is stochastic and depends on local cytosolic Ca 2+ , JSR Ca 2+ , and allosteric coupling, (2) IP 3 R2 gating is stochastic and depends primarily on local cytosolic Ca 2+ and IP 3 , and the (3) RyR2 has a larger single channel Ca 2+ current than the IP 3 R2. Our simulations show that Ca 2+ spark probability increases with increasing IP 3 R2 expression in HF CRUs and IP 3 R2 expression mitigates differences in mean duration of and mean total Ca 2+ released during Ca 2+ sparks observed in simulations in which HF is modeled as fragmentation and dispersion of RyR2s within CRUs alone. Overall, this mathematical modeling study suggests that increased IP 3 R2 expression in the context of HF may contribute to pro-arrhythmic Ca 2+ signaling via increased Ca 2+ spark frequency but may also serve a compensatory function by countering changes in Ca 2+ spark morphology that arise due to RyR2 remodeling within CRUs in HF.
Jones et al. (Wed,) conducted a other in Heart failure (computational model). Increased IP3R2 expression and RyR2 fragmentation (Heart Failure model) vs. Healthy control model was evaluated on Ca2+ spark fidelity and multi-spark events. Mathematical modeling demonstrated that increased IP3R2 expression in heart failure calcium release units increases calcium spark fidelity and facilitates pro-arrhythmic multi-spark events.