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Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII‐constitutive phosphorylation of RyR2 at site S2814

Mice with Ca2+–calmodulin‐dependent protein kinase (CaMKII) constitutive pseudo‐phosphorylation of the ryanodine receptor RyR2 at Ser2814 (S2814D+/+ mice) exhibit a higher open probability of RyR2, higher sarcoplasmic reticulum (SR) Ca2+ leak in diastole and increased propensity to arrhythmias under stress conditions. We generated phospholamban (PLN)‐deficient S2814D+/+ knock‐in mice by crossing two colonies, S2814D+/+ and PLNKO mice, to test the hypothesis that PLN ablation can prevent the propensity to arrhythmias of S2814D+/+ mice. PLN ablation partially rescues the altered intracellular Ca2+ dynamics of S2814D+/+ hearts and myocytes, but enhances SR Ca2+ sparks and leak on confocal microscopy. PLN ablation diminishes ventricular arrhythmias promoted by CaMKII phosphorylation of S2814 on RyR2. PLN ablation aborts the arrhythmogenic SR Ca2+ waves of S2814D+/+ and transforms them into non‐propagating events. A mathematical human myocyte model replicates these results and predicts the increase in SR Ca2+ uptake required to prevent the arrhythmias induced by a CaMKII‐dependent leaky RyR2.