A hypothetical model illustrating the Ca²⁺ signaling pathways implicated in POAF. Cytosolic Ca²⁺ handling abnormalities in atrial myocytes have been suggested to play an important role in the initiation and maintenance of atrial fibrillation. (A) Fakuade et al. reported that sarcoplasmic reticulum (SR) Ca²⁺ leak and ryanodine receptor channel (RyR2) function in atrial myocytes. Reduced SERCA-mediated Ca²⁺ reuptake into the SR is a major contributor to impaired preoperative atrial contractile function and the pre-existing arrhythmogenic substrate in patients developing POAF. Therefore, modulation of SERCA activity may represent a novel mechanistic target to prevent the development of POAF. (B) With higher dosing ratios of protamine-to-heparin, the residual protamine may activate RyR2 dose-dependently, followed by RyR2-mediated Ca²⁺ leak, resulting in increased cytosolic Ca²⁺ and POAF. Therefore, dosing ratios of protamine-to-heparin may be an important determinant in the development of POAF in addition to reduced SERCA-mediated Ca²⁺ reuptake into the SR described in Figure 1A. POAF, postoperative atrial fibrillation; SR, sarcoplasmic reticulum; SERCA, sarcoplasmic reticulum calcium ATPase (sarcoplasmic reticulum calcium pump).