Approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca²⁺ release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca²⁺ remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca²⁺/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias.

Mice in which the S2814 Ca²⁺/calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca²⁺ release events, resulting in reduced sarcoplasmic reticulum Ca²⁺ load on confocal microscopy. These Ca²⁺ release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts without arrhythmias; however, they develop sustained ventricular tachycardia and sudden cardiac death on catecholaminergic provocation by caffeine/epinephrine or programmed electric stimulation. Young S2814D mice have a significant predisposition to sudden arrhythmogenic death after transverse aortic constriction surgery. Finally, genetic ablation of the Ca²⁺/calmodulin-dependent protein kinase II site on RyR2 (S2814A) protects mutant mice from pacing-induced arrhythmias versus wild-type mice after transverse aortic constriction surgery.

Our results suggest that Ca²⁺/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca²⁺ release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure.