Sarcoplasmic reticulum luminal [Ca2+] regulates the spontaneous Ca2+ release events and consequently arrhythmia

The role that sarcoplasmic reticulum (SR) luminal Ca²⁺ concentration plays in regulating ryanodine receptors (RyRs) is considered to be very important in process of cardiac excitation-contraction coupling. Here we developed a multi-scale mathematical model by coupling a two-dimensional spatio-temporal Ca²⁺ reaction-diffusion model with an action potential model of the ventricular myocyte. The simulation results showed that 1) the frequency of spontaneous sparks increased when SR Ca²⁺ content was elevated; 2) when SR Ca²⁺ was overloaded, spontaneous Ca²⁺ waves might occur without any external stimulus, and 3) once formed, the propagation of Ca²⁺ waves was accelerated as the SR Ca²⁺ content increased. Moreover, those spontaneously occurred Ca²⁺ release events elevated cytoplasmic [Ca²⁺]i and then activated inward currents which might cause a delayed afterdepolarization (DAD).