Central Illustration.

Proposed mechanisms for RyR2-associated catecholaminergic polymorphic ventricular tachycardia (CPVT), exon 3 deletion syndrome (E3DS), and calcium release deficiency syndrome (CRDS). The different thresholds for store overload-induced Ca²⁺ release (SOICR) and Ca²⁺ release termination and the free sarcoplasmic reticulum (SR) luminal Ca²⁺ levels in CPVT, E3DS, or CRDS associated with RyR2 mutations are illustrated in the resting state (Rest, left panels) and in the stress states (Stress, right panels). The normal thresholds for SOICR and Ca²⁺ release termination are depicted as red and yellow dashed bars, respectively. The reduced or elevated SOICR thresholds as a consequence of CPVT, E3DS, or CRDS RyR2 mutations are depicted as solid red bars. The reduced threshold for Ca²⁺ release termination as a consequence of E3DS RyR2 mutations are depicted as solid yellow bars. The SR free luminal Ca²⁺ level is represented as a blue area. The yellow areas above the blue areas in the right panels represent an elevation, even if only transient, in the free SR luminal Ca²⁺ levels, which, we propose, will occur when sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) activity is enhanced by catecholamines or during the long-burst, long-pause, short-coupled (LBLPS) programed electrical stimulation. When the SR-free luminal Ca²⁺ level surpasses, even transiently, the reduced SOICR threshold in the case of CPVT and E3DS, SOICR occurs, leading to a spillover of SR Ca²⁺ that can trigger spontaneous Ca²⁺ release, delayed afterdepolarizations (DADs) and ventricular arrhythmias (VAs). The reduced termination threshold in the case of E3DS will increase the fractional Ca²⁺ release, resulting in large Ca²⁺ transients at rest (left panels) and stress (right panels) that may promote cardiomyopathies in addition to cardiac arrhythmia. In the case of CRDS, the elevated SOICR threshold prevents spontaneous SR Ca²⁺ leak, leading to markedly elevated SR Ca²⁺ load upon LBLPS electrical stimulation and subsequently large Ca²⁺ transients that promote early afterdepolarizations (EADs), reentrant activity, and ventricular arrhythmias.