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 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.
Grandi
Eleonora
E
Biomedical Engineering Laboratory, Department of Electronics, Computer Science and Systems, University of Bologna, Bologna, Italy.
Puglisi
Jose L
JL
Wagner
Stefan
S
Maier
Lars S
LS
Severi
Stefano
S
Bers
Donald M
DM
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D003198:Computer Simulation; D006352:Heart Ventricles / Q000166:cytology; D015640:Ion Channel Gating / Q000502:physiology*; D008390:Markov Chains; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000502:physiology*; D011817:Rabbits; D015222:Sodium Channels / Q000502:physiology*; D016276:Ventricular Function
D015220:Calcium Channels; D015222:Sodium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
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