Role of ryanodine receptor cooperativity in Ca-wave-mediated triggered activity in cardiomyocytes.

Ca waves are known to trigger delayed after-depolarizations that can cause malignant cardiac arrhythmias. However, modelling Ca waves using physiologically realistic models has remained a major challenge. Existing models with low Ca sensitivity of ryanodine receptors (RyRs) necessitate large release currents, leading to an unrealistically large Ca transient amplitude incompatible with the experimental observations. Consequently, current physiologically detailed models of delayed after-depolarizations resort to unrealistic cell architectures to produce Ca waves with a normal Ca transient amplitude. Here, we address these challenges by incorporating RyR cooperativity into a physiologically detailed model with a realistic cell architecture. We represent RyR cooperativity phenomenologically through a Hill coefficient within the sigmoid function of RyR open probability. Simulations in permeabilized myocytes with high Ca sensitivity reveal that a sufficiently large Hill coefficient is required for Ca wave propagation via the fire-diffuse-fire mechanism. In intact myocytes, propagating Ca waves can occur only within an intermediate Hill coefficient range. Within this range, the spark rate is neither too low, enabling Ca wave propagation, nor too high, allowing for the maintenance of a high sarcoplasmic reticulum load during diastole of the action potential. Moreover, this model successfully replicates other experimentally observed manifestations of Ca-wave-mediated triggered activity, including phase 2 and phase 3 early after-depolarizations and high-frequency voltage-Ca oscillations. These oscillations feature an elevated take-off potential with depolarization mediated by the L-type Ca current. The model also sheds light on the roles of luminal gating of RyRs and the mobile buffer ATP in the genesis of these arrhythmogenic phenomena. KEY POINTS: Existing mathematical models of Ca waves use an excessively large Ca-release current or unrealistic diffusive coupling between release units. Our physiologically realistic model, using a Hill coefficient in the ryanodine receptor (RyR) gating function to represent RyR cooperativity, addresses these limitations and generates organized Ca waves at Hill coefficients ranging from ∼5 to 10, as opposed to the traditional value of 2. This range of Hill coefficients gives a spark rate neither too low, thereby enabling Ca wave propagation, nor too high, allowing for the maintenance of a high sarcoplasmic reticulum load during the plateau phase of the action potential. Additionally, the model generates Ca-wave-mediated phase 2 and phase 3 early after-depolarizations, and coupled membrane voltage with Ca oscillations mediated by the L-type Ca current. This study suggests that pharmacologically targeting RyR cooperativity could be a promising strategy for treating cardiac arrhythmias linked to Ca-wave-mediated triggered activity.