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

¹ Loyola University Med. Ctr.
² Georg-August-Universitaet Goettingen
³ University of Bologna

^* To whom correspondence should be addressed. E-mail: dbers{at}lumc.edu.

Submitted on June 12, 2007
Revised on June 29, 2007
Accepted on 1 August 2007

	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 (LQT3) and Brugada Syndrome (BrS). 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 in 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, slows recovery from inactivation (all loss of function effects), but also enhances late non-inactivating 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 (LQT3). 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 (BrS). 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 prolong and shorten AP duration individually. 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.

Key Words: Na channel, arrhythmias, computer model, heart failure