In conditions with abnormally increased activity of the cardiac ryanodine receptor (RyR2), Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) can contribute to a further destabilization of RyR2 that results in triggered arrhythmias. Therefore, inhibition of CaMKII in such conditions has been suggested as a strategy to suppress RyR2 activity and arrhythmias. However, suppression of RyR2 activity can lead to the development of arrhythmogenic Ca²⁺ alternans. The aim of this study was to test whether the suppression of RyR2 activity caused by inhibition of CaMKII increases propensity for Ca²⁺ alternans. We studied spontaneous Ca²⁺ release events and Ca²⁺ alternans in isolated left ventricular cardiomyocytes from mice carrying the gain-of-function RyR2 mutation RyR2-R2474S and from wild-type mice. CaMKII inhibition by KN-93 effectively decreased the frequency of spontaneous Ca²⁺ release events in RyR2-R2474S cardiomyocytes exposed to the β-adrenoceptor agonist isoprenaline. However, KN-93-treated RyR2-R2474S cardiomyocytes also showed increased propensity for Ca²⁺ alternans and increased Ca²⁺ alternans ratio compared with both an inactive analog of KN-93 and with vehicle-treated controls. This increased propensity for Ca²⁺ alternans was explained by prolongation of Ca²⁺ release refractoriness. Importantly, the increased propensity for Ca²⁺ alternans in KN-93-treated RyR2-R2474S cardiomyocytes did not surpass that of wild type. In conclusion, inhibition of CaMKII efficiently reduces spontaneous Ca²⁺ release but promotes Ca²⁺ alternans in RyR2-R2474S cardiomyocytes with a gain-of-function RyR2 mutation. The dominant effect in RyR2-R2474S is to reduce spontaneous Ca²⁺ release, which supports this intervention as a therapeutic strategy in this specific condition. However, future studies on CaMKII inhibition in conditions with increased propensity for Ca²⁺ alternans should include investigation of both phenomena.NEW & NOTEWORTHY Genetically increased RyR2 activity promotes arrhythmogenic Ca²⁺ release. Inhibition of CaMKII suppresses RyR2 activity and arrhythmogenic Ca²⁺ release. Suppression of RyR2 activity prolongs refractoriness of Ca²⁺ release. Prolonged refractoriness of Ca²⁺ release leads to arrhythmogenic Ca²⁺ alternans. CaMKII inhibition promotes Ca²⁺ alternans by prolonging Ca²⁺ release refractoriness.

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