Ca-calmodulin-dependent protein kinase II (CaMKII) was recently shown to alter 
Na(+) channel gating and recapitulate a human Na(+) channel genetic mutation 
that causes an unusual combined arrhythmogenic phenotype in patients: 
simultaneous long QT syndrome and Brugada syndrome. CaMKII is upregulated in 
heart failure where arrhythmias are common, and CaMKII inhibition can reduce 
arrhythmias. Thus, CaMKII-dependent channel modulation may contribute to 
acquired arrhythmic disease. We developed a Markovian Na(+) channel model 
including CaMKII-dependent changes, and incorporated it into a comprehensive 
myocyte action potential (AP) model with Na(+) and Ca(2+) transport. CaMKII 
shifts Na(+) current (I(Na)) availability to more negative voltage, enhances 
intermediate inactivation, and slows recovery from inactivation (all 
loss-of-function effects), but also enhances late noninactivating I(Na) (gain of 
function). At slow heart rates, with long diastolic time for I(Na) recovery, 
late I(Na) is the predominant effect, leading to AP prolongation (long QT 
syndrome). At fast heart rates, where recovery time is limited and APs are 
shorter, there is little effect on AP duration, but reduced availability 
decreases I(Na), AP upstroke velocity, and conduction (Brugada syndrome). CaMKII 
also increases cardiac Ca(2+) and K(+) currents (I(Ca) and I(to)), complicating 
CaMKII-dependent AP changes. Incorporating I(Ca) and I(to) effects individually 
prolongs and shortens AP duration. Combining I(Na), I(Ca), and I(to) effects 
results in shortening of AP duration with CaMKII. With transmural heterogeneity 
of I(to) and I(to) downregulation in heart failure, CaMKII may accentuate 
dispersion of repolarization. This provides a useful initial framework to 
consider pathways by which CaMKII may contribute to arrhythmogenesis.