Of note, selective genetic inhibition of CaMKII-dependent RyR2-hyperphosphorylation (RyR2-Ser2814Ala) also reduced the incidence of rapid-pacing-induced AF in mice where a vulnerable substrate was created using stimulation with the muscarinic-receptor agonist carbachol, and pacing-induced AF in mice deficient of FKBP12.6 (Chelu et al., 2009; Li et al., 2012), strongly suggesting that CaMKII-dependent RyR2 hyperphosphorylation and associated Ca2+-handling abnormalities are critical AF-promoting factors (Dobrev et al., 2011). This evidence concerns the gene RYR2 and atrial fibrillation.