Aim: 

Increased frequency of diastolic Ca sparks supposedly contributes to the increased propensity to arrhythmias in the failing myocardium. Another type of RyR malfunction that occurs in stress-induced arrhythmias is related to mutated RyRs. Both pathological conditions transpire at the cellular level as diastolic calcium waves. Several molecular mechanisms leading to calcium wave formation have been implicated in RyR dysregulation; these include changes in the interaction of RyR with FKBP12.6, in intramolecular interactions within RyRs, in the inhibition of the channel by Mg²⁺ ions, or in the RyR activation by luminal Ca²⁺ .

Methods: 

We have tested the effects of these regulatory mechanisms, as well as the effect of RyR refractoriness in a mathematical model of calcium spark generation that incorporated various models of RyR gating.

Results: 

The apparent sensitivity of RyRs to cytosolic Ca²⁺, and thus also diastolic spark frequency, was changed by all regulatory mechanisms in a similar way but with different sensitivity. Increased spark frequency alone was not sufficient for initiation and propagation of arrhythmogenic calcium waves. Calcium wave formation was strongly dependent on the amplitude and duration of calcium sparks and on the rate of RyR recovery from refractoriness.

Conclusions: 

All proposed molecular mechanisms may underlie the increase of diastolic calcium spark frequency. Importantly, however, wave generation required increased amount of released calcium during a spark and/or faster recovery of RyRs, which may be achieved only upon adrenergic stimulation, i.e., when this condition occurs in vivo.