Role of RyR cooperativity in Ca²⁺-wave-mediated triggered activity in cardiomyocytes

Ca²⁺ waves are known to trigger delayed afterdepolarizations (DADs) that can cause malignant cardiac arrhythmias. However, modeling Ca²⁺ waves using physiologically realistic models has remained a major challenge. Existing models with low Ca²⁺ sensitivity of RyRs necessitate large release currents, leading to an unrealistically large Ca²⁺ transient (CaT) amplitude incompatible with the experimental observations. Consequently, current physiologically detailed models of DADs resort to unrealistic cell architectures to produce Ca²⁺ waves with a normal CaT 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 Ca²⁺ sensitivity reveal that a sufficiently large Hill coefficient is required for Ca²⁺ wave propagation via the fire-diffuse-fire mechanism. In intact myocytes, propagating Ca²⁺ waves can only occur within an intermediate Hill coefficient range. Within this range, the spark rate is neither too low, enabling Ca²⁺ wave propagation, nor too high, allowing for the maintenance of a high SR load during diastole of the action potential. Moreover, this model successfully replicates other experimentally observed manifestations of Ca²⁺-wave-mediated triggered activity, including phase 2 and phase 3 early afterdepolarizations, and high-frequency voltage-Ca²⁺ oscillations. These oscillations feature an elevated take-off potential with depolarization mediated by the L-type Ca²⁺ 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.