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 CaMKIIdelta(C) on Na(+) current (I(Na)) 
in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch 
clamp). Both acute and chronic CaMKIIdelta(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). CaMKIIdelta(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 CaMKIIdelta(C) 
overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na(+) 
channels. In vivo, transgenic CaMKIIdelta(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 
CaMKIIdelta(C) activity predisposed to VT. Thus, CaMKII-dependent regulation of 
Na(+) channel function may contribute to arrhythmogenesis in HF.