Figure 3.

Simplified schematic to illustrate the proposed pathways linking RyR2 loss-of-function (LoF, red) and gain-of-function (GoF, blue) abnormalities to pro-arrhythmic behavior. In GoF, excess Ca²⁺ leak leads to diastolic Ca²⁺ waves and DADs which tend to decrease the Ca²⁺ load. In LoF, evoked Ca²⁺ release is impaired resulting in Ca²⁺ loading and less Ca²⁺-dependent inactivation (CDI) of I_Ca, ultimately resulting in prolonged systolic Ca²⁺ release and EADs. Increasing Ca²⁺ load worsens Ca²⁺ regulation and hastens arrhythmia development.