The mechanisms underlying Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)-induced arrhythmias in ischemia-reperfusion (I/R) are not fully understood. We tested the hypothesis that CaMKII increases late Na⁺ current ( I_Na,L) via phosphorylation of Na_v1.5 at Ser⁵⁷¹ during I/R, thereby increasing arrhythmia susceptibility. To test our hypothesis, we studied isolated, Langendorff-perfused hearts from wild-type (WT) mice and mice expressing Na_v channel variants Na_v1.5-Ser571E (S571E) and Na_v1.5-Ser571A (S571A). WT hearts showed a significant increase in the levels of phosphorylated CaMKII and Na_v1.5 at Ser⁵⁷¹ [p-Na_v1.5(S571)] after 15 min of global ischemia (just before the onset of reperfusion). Optical mapping experiments revealed an increase in action potential duration (APD) and APD dispersion without changes in conduction velocity during I/R in WT and S571E compared with S571A hearts. At the same time, WT and S571E hearts showed an increase in spontaneous arrhythmia events (e.g., premature ventricular contractions) and an increase in the inducibility of reentrant arrhythmias during reperfusion. Pretreatment of WT hearts with the Na⁺ channel blocker mexiletine (10 μM) normalized APD dispersion and reduced arrhythmia susceptibility during I/R. We conclude that CaMKII-dependent phosphorylation of Na_v1.5 is a crucial driver for increased I_Na,L, arrhythmia triggers, and substrate during I/R. Selective targeting of this CaMKII-dependent pathway may have therapeutic potential for reducing arrhythmias in the setting of I/R. NEW & NOTEWORTHY Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of Na_v1.5 at Ser⁵⁷¹ leads to a prolongation of action potential duration (APD), increased APD dispersion, and increased arrhythmia susceptibility after ischemia-reperfusion in isolated mouse hearts. Genetic ablation of the CaMKII-dependent phosphorylation site Ser⁵⁷¹ on Na_v1.5 or low-dose mexiletine (to inhibit late Na⁺ current) reduced APD dispersion, arrhythmia triggers, and ventricular tachycardia inducibility.

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