Simulation of Ca-Calmodulin-Dependent Protein Kinase II on Rabbit Ventricular Myocyte Ion Currents and Action Potentials

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 Ca2+ transport. CaMKII shifts Na+ current (INa) availability to more negative voltage, enhances intermediate inactivation, and slows recovery from inactivation (all loss-of-function effects), but also enhances late noninactivating INa (gain of function). At slow heart rates, with long diastolic time for INa recovery, late INa 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 INa, AP upstroke velocity, and conduction (Brugada syndrome). CaMKII also increases cardiac Ca2+ and K+ currents (ICa and Ito), complicating CaMKII-dependent AP changes. Incorporating ICa and Ito effects individually prolongs and shortens AP duration. Combining INa, ICa, and Ito effects results in shortening of AP duration with CaMKII. With transmural heterogeneity of Ito and Ito 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.