In heart failure (HF), Ca 2+ /calmodulin kinase II (CaMKII) expression is increased. Altered Na + channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na + channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKIIδ C on Na + current (I Na ) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIδ C overexpression shifted voltage dependence of Na + channel availability by -6 mV (P < 0.05), and the shift was Ca 2+ dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2-related inhibitory peptide [AIP] or KN93). CaMKIIδ C markedly increased persistent (late) inward I Na and intracellular Na + concentration (as measured by the Na + indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKIIδ C overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na + channels. In vivo, transgenic CaMKIIδ C overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na + channels. This alters I Na gating to reduce availability at high heart rate, while enhancing late I Na (which could prolong action potential duration). In mice, enhanced CaMKIIδ C activity predisposed to VT. Thus, CaMKIIdependent regulation of Na + channel function may contribute to arrhythmogenesis in HF.

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Abstract-The predominant cardiac Ca 2ϩ /calmodulin-dependent protein kinase (CaMK) is CaMKII␦. Here we acutely overexpress CaMKII␦ C using adenovirus-mediated gene transfer in adult rabbit ventricular myocytes. This circumvents confounding adaptive effects in CaMKII␦ C transgenic mice. CaMKII␦ C protein expression and activation state (autophosphorylation) were increased 5-to 6-fold. Basal twitch contraction amplitude and kinetics (1 Hz) were not changed in CaMKII␦ C versus LacZ expressing myocytes. However, the contraction-frequency relationship was more negative, frequency-dependent acceleration of relaxation was enhanced ( 0.5Hz / 3Hz ϭ2.14Ϯ0.10 versus 1.87Ϯ0.10), and peak Ca 2ϩ current (I Ca ) was increased by 31% (Ϫ7.1Ϯ0.