Advanced age is a well‐recognized predisposition to atrial fibrillation (AF). However, the cellular electrophysiological changes that underlie the heightened susceptibility to AF in aged individuals remain poorly understood. Sarcoplasmic reticulum (SR) Ca²⁺ leak that results from posttranslational modification of type 2 ryanodine receptor channels (RyR2) has been implicated in arrhythmogenesis. We hypothesize that aging alters atrial myocytes Ca²⁺ homeostasis and RyR2 function, which create a substrate for AF initiation.

We examined the susceptibility to AF in aged (24 months) and young adult (4–5 months) mice using an intraesophageal atrial electrical stimulation protocol. Aged mice showed significant higher AF induction rate (43.3%, n = 30) than young adults (8.8%, n = 34, P < 0.01). In accordance with these in vivo findings, significantly increased diastolic SR Ca²⁺ leak and arrhythmogenic Ca²⁺ activities with reduced SR Ca²⁺ content were observed in aged atrial myocytes. Western blot showed RyR2 oxidation and phosphorylation at Ser2814 (Ca²⁺/calmodulin‐dependent protein kinase II [CaMKII] site), but not phosphorylation at Ser2808 (protein kinase A [PKA] and CaMKII site), were increased in aged atrial myocytes. The selective CaMKII inhibitor (KN‐93), as well as the antioxidant reagent (DTT) reversed the diastolic Ca²⁺ leak and the frequency of spontaneous Ca²⁺ transients in aged atrial myocytes, whereas PKA inhibition with H‐89 was ineffective.

Aging increases both the oxidation and CaMKII‐phosphorylation of RyR2, which result in diastolic SR Ca²⁺ leak and facilitate AF initiation. These results contribute to the electrophysiological remodeling of aged atria and suggest a therapeutic strategy for AF treatment in aging.