title: 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 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.
authors: Biomedical Engineering Laboratory, Department of Electronics, Computer Science and Systems, University of Bologna, Bologna, Italy.
authors: Eleonora
authors: E
authors: Grandi
authors: Jose L
authors: JL
authors: Puglisi
authors: Stefan
authors: S
authors: Wagner
authors: Lars S
authors: LS
authors: Maier
authors: Stefano
authors: S
authors: Severi
authors: Donald M
authors: DM
authors: Bers
mesh_terms: 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
chemical_list: D015220:Calcium Channels; D015222:Sodium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
references: Cardiovasc Res. 2007 Mar 1;73(4):631-40
references: 17157285
references: Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H56-65
references: 16980337
references: Biophys J. 2008 Nov 15;95(10):4597-612
references: 18689454
references: Circ Res. 1999 Oct 29;85(9):810-9
references: 10532949
references: Cardiovasc Res. 2000 Jan 14;45(2):397-409
references: 10728360
references: Circ Res. 2000 May 12;86(9):E91-7
references: 10807877
references: J Mol Cell Cardiol. 2001 May;33(5):851-72
references: 11343410
references: Circ Res. 2001 Jun 8;88(11):1159-67
references: 11397782
references: Basic Res Cardiol. 2001 Nov;96(6):517-27
references: 11770069
references: Circ Res. 2002 Feb 8;90(2):182-9
references: 11834711
references: Circulation. 2002 Mar 12;105(10):1208-13
references: 11889015
references: Circ Res. 2002 May 3;90(8):889-96
references: 11988490
references: Circulation. 2002 May 28;105(21):2543-8
references: 12034663
references: Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H490-500
references: 12124193
references: Circulation. 2002 Jul 23;106(4):447-53
references: 12135944
references: Circulation. 2002 Sep 3;106(10):1288-93
references: 12208807
references: J Clin Invest. 2002 Nov;110(9):1251-62
references: 12417563
references: Circ Res. 2003 May 2;92(8):904-11
references: 12676813
references: Circ Res. 2003 May 2;92(8):912-9
references: 12676814
references: Circulation. 2003 Aug 26;108(8):965-70
references: 12925462
references: Biochem J. 2004 Jan 15;377(Pt 2):357-66
references: 14556649
references: J Mol Cell Cardiol. 2004 Jan;36(1):67-74
references: 14734049
references: Cardiovasc Res. 2004 Aug 15;63(3):476-86
references: 15276473
references: J Physiol. 2004 Sep 1;559(Pt 2):593-609
references: 15243136
references: Biophys J. 2004 Nov;87(5):3351-71
references: 15347581
references: Am J Physiol. 1994 Sep;267(3 Pt 2):H982-93
references: 8092302
references: Circ Res. 1994 Nov;75(5):854-61
references: 7923631
references: Am J Physiol. 1996 May;270(5 Pt 2):H1772-8
references: 8928885
references: Cardiovasc Res. 1999 Apr;42(1):254-61
references: 10435018
references: Circulation. 2004 Nov 16;110(20):3168-74
references: 15505083
references: J Mol Cell Cardiol. 2005 Mar;38(3):475-83
references: 15733907
references: Nat Med. 2005 Apr;11(4):409-17
references: 15793582
references: Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2077-87
references: 15637125
references: Europace. 2005 Sep;7 Suppl 2:3-9
references: 16102498
references: Biophys J. 2005 Dec;89(6):4096-110
references: 16169970
references: Circ Res. 2005 Dec 9;97(12):1314-22
references: 16269653
references: Cardiovasc Res. 2006 Jan;69(1):116-27
references: 16223473
references: Circ Res. 2006 Feb 3;98(2):235-44
references: 16373600
references: J Cardiovasc Electrophysiol. 2006 May;17 Suppl 1:S151-S157
references: 16686672
references: Circ Res. 2006 Aug 18;99(4):398-406
references: 16840718
references: Am J Physiol Heart Circ Physiol. 2006 Oct;291(4):H1978-87
references: 16648177
references: Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2617-29
references: 16829642
references: Circ Res. 2006 Nov 10;99(10):1092-9
references: 17038644
references: J Clin Invest. 2006 Dec;116(12):3127-38
references: 17124532
references: Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H2854-66
references: 17277017