Simulation of Ca-calmodulin-dependent protein kinase II on rabbit ventricular myocyte ion currents and action potentials

Abstract

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 (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 Ca2+ 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.