Computational Evidence Of Centripetal Propagating "Ca2+-Induced-Ca2+-Release" In Stimulated Cardiac Purkinje Cells

Rationale: Cai-variations in Purkinje cells (Pcells) can affect cardiac conduction by generating action potentials in Purkinje fibers thereby promoting arrhythmias. The system underlying Cai-variations in Pcells is still unknown. Upon stimulation, this system mediates Cai-elevation propagating from the periphery to the cell centre (Fig.1A). Ca2+-diffusion from initial Ca2+-release by the peripheral endoplasmic reticulum (ER) could explain this centripetal Ca2+-propagation (CCP). Alternatively, study of Pcells suggest a consecutive “Ca2+-induced-Ca2+-release” (CICR) from 3 adjacent ER regions expressing distinct Ca2+-channels. To determine whetherCCP is mediated by diffusion only or “CICR-diffusion-CICR”, a system of nonlinear parabolic partial differential equations was developed to simulate Ca2+-dynamics in a 2D rectangular array comprising 3 adjacent Ca2+-release regions R1, R2, R3 (Fig.1B.b). Simulated CCP was compared against CCP measured in stimulated porcine Pcells. Results:The model accurately reproduced CCP (Fig.1) when CICR was activated in R2 and R3. When CICR was off in R2 and/or R3 and only Ca2+-diffusion was considered, CCP collapsed shortly after Ca2+-release in R1. Conclusion: our results are consistent with a mechanism of consecutive ER-Ca2+-releases propagating centripetally by CICR-diffusion-CICR. The intermediate region R2 appears to be a critical functional link in the process.View Large Image | View Hi-Res Image | Download PowerPoint Slide