Fig. 6. Proposed mechanism of CPVT-related RyR2 variants, other gain-of-function mutants, and heart failure.

(A) Schematic representation of the normal function of RyR2. (B) Schematic representation of the CPVT-related Ca²⁺ leak during diastole under intense exercise or stress conditions. In the case of CPVT variants, the resting state is already in a primed state. This correlates with the higher open probability during exercise or stress conditions, which results in opening during diastole, afterdepolarizations, arrhythmias, and sudden cardiac death. This pathological state can be reversed by treatment with the Rycal ARM210 (R). This basal primed state scenario could be a shared mechanism among other RyR1 and RyR2 gain-of-function mutants. (C) Schematic representation of the heart failure–related primed state and Ca²⁺ leak. The heart failure–related primed state remains hypothetical as no structure has been solved yet.