Sadredini M, Haugsten Hansen M, Frisk M, Louch WE, Lehnart SE, Sjaastad I, Stokke MK
American Journal of Physiology. Heart and Circulatory Physiology
Am J Physiol Heart Circ Physiol. 2021 Jul 16.
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.
Aim: To test whether suppression of RyR2 activity caused by inhibition of CaMKII increases propensity for Ca2+ alternans.
Methods and results: 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.
Conclusions: 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.