Figure 2.

Shortened Ca²⁺ signalling refractoriness in heart disease. (A) Schematic illustration of time-dependent processes occurring between systolic SR Ca²⁺ depletion and onset of diastolic spontaneous Ca²⁺ wave (DCW). This latency is composed of a refractory period, reflecting recovery from store-dependent deactivation, and an idle period required for the transition of stochastic release events through functionally recovered RyR2s to regenerating Ca2+ waves. A shorter time delay between systolic Ca²⁺ release and DCW in diseased myocytes is attributed to reduced refractoriness of the SR Ca²⁺ release determined by recording the restitution of the Ca²⁺ transient amplitude measured with a two-pulse protocol. (B) Shortened refractoriness in post-myocardial infarction (MI) myocytes is associated with altered regulation of Ca²⁺ release by SR luminal Ca²⁺ resulting in a diminished capability of reduced SR Ca²⁺ to inhibit RyR2 activity during diastole. Fast restitution of Ca²⁺ transient (C) and abnormally high activity of RyR2 (D) observed in diseased hearts can be normalized by treatment with reducing agents monopropyonylglycine (MPG; C) and dithiothreitol (DTT; D and E), respectively. Adapted from Belevych et al.^27,54 and Terentyev et al.⁶²