Abstract 361: In Silico Assessment of the Effect of Ca-Calmodulin Dependent Protein Kinase II (CaMKII) on Rabbit Ventricular Ion Currents and Action Potential
CaMKII alters cardiac Na channel gating very much like a human Nav1.5 mutation (1795insD) that causes combined long QT (LQTS) and Brugada (BrS) syndromes. CaMKII shifts Na current (INa) availability to more negative voltage, enhances intermediate inactivation, and slows recovery from inactivation (loss of function), but also enhances late INa (gain of function). CaMKII also modulates cardiac Ca & K currents, increasing both ICa (larger peak and slower inactivation) and Ito (larger peak and faster recovery from inactivation). As CaMKII is upregulated in heart failure (HF) where arrhythmias are common, these CaMKII effects may contribute to arrhythmogenesis. We tested the individual and combined effects of these alterations in silico. We developed an INa Markovian model, and modified our existing ICa and Ito, incorporating them into the comprehensive Chicago rabbit myocyte Ca and action potential (AP) model. When CaMKII effects on INa only were considered, simulation indicates that at low heart rates enhanced late INa is predominant causing AP prolongation (LQTS). At high heart rates, the limited recovery time reduces INa availability. This has little effect on AP duration (APD), but decreases AP upstroke and conduction velocity (BrS). CaMKII effects on ICa alone cause AP prolongation (at all heart rates), while Ito effects shorten APD (at all heart rates). Combining these 3 effects (or Ito with either INa or ICa) shortens APD. However, where Ito density is low (e.g. in endocardial or HF myocytes), the composite CaMKII effects produces acquired LQTS. We concluded that CaMKII effects on INa, ICa and Ito combined with transmural heterogeneity of Ito and Ito downregulation in HF may accentuate dispersion of repolarization and predispose to reentrant arrhythmias. This provides a useful framework to consider pathways by which CaMKII may contribute to arrhythmogenesis and highlights novel potential therapeutic targets.