title: Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure.
abstract: BACKGROUND
  Slowed Na⁺ current (INa) decay and enhanced late INa (INa-L) prolong the action potential duration (APD) and contribute to early afterdepolarizations. Cardiac resynchronization therapy (CRT) shortens APD compared with dyssynchronous heart failure (DHF); however, the role of altered Na⁺ channel gating in CRT remains unexplored.
  
  
  RESULTS
  Adult dogs underwent left-bundle branch ablation and right atrial pacing (200 beats/min) for 6 weeks (DHF) or 3 weeks followed by 3 weeks of biventricular pacing at the same rate (CRT). INa and INa-L were measured in left ventricular myocytes from nonfailing, DHF, and CRT dogs. DHF shifted voltage-dependence of INa availability by -3 mV compared with nonfailing, enhanced intermediate inactivation, and slowed recovery from inactivation. CRT reversed the DHF-induced voltage shift of availability, partially reversed enhanced intermediate inactivation but did not affect DHF-induced slowed recovery. DHF markedly increased INa-L compared with nonfailing. CRT dramatically reduced DHF-induced enhanced INa-L, abbreviated the APD, and suppressed early afterdepolarizations. CRT was associated with a global reduction in phosphorylated Ca²⁺/Calmodulin protein kinase II, which has distinct effects on inactivation of cardiac Na⁺ channels. In a canine AP model, alterations of INa-L are sufficient to reproduce the effects on APD observed in DHF and CRT myocytes.
  
  
  CONCLUSIONS
  CRT improves DHF-induced alterations of Na⁺ channel function, especially suppression of INa-L, thus, abbreviating the APD and reducing the frequency of early afterdepolarizations. Changes in the levels of phosphorylated Ca²⁺/Calmodulin protein kinase II suggest a molecular pathway for regulation of INa by biventricular pacing of the failing heart.
authors: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Takeshi
authors: T
authors: Aiba
authors: Andreas S
authors: AS
authors: Barth
authors: Geoffrey G
authors: GG
authors: Hesketh
authors: Yasmin L
authors: YL
authors: Hashambhoy
authors: Khalid
authors: K
authors: Chakir
authors: Richard S
authors: RS
authors: Tunin
authors: Joseph L
authors: JL
authors: Greenstein
authors: Raimond L
authors: RL
authors: Winslow
authors: David A
authors: DA
authors: Kass
authors: Gordon F
authors: GF
authors: Tomaselli
mesh_terms: D000818:Animals; D058406:Cardiac Resynchronization Therapy / Q000379:methods*; D003198:Computer Simulation; D004195:Disease Models, Animal; D004285:Dogs; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology; D006333:Heart Failure / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D015222:Sodium Channels / Q000378:metabolism*; D015996:Survival Rate; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; D015222:Sodium Channels
keywords: Na+ channels; arrhythmias; cardiac resynchronization therapy; electrophysiology; heart failure
references: Circ Res. 2007 Nov 26;101(11):1146-54
references: 17901361
references: Cardiovasc Res. 2005 Jul 1;67(1):77-86
references: 15885674
references: Circulation. 2004 Aug 24;110(8):904-10
references: 15302796
references: Circ Res. 2011 Mar 4;108(5):555-65
references: 21252154
references: Circulation. 1997 Sep 16;96(6):2038-47
references: 9323097
references: Circ Res. 1989 Feb;64(2):389-97
references: 2536304
references: Circulation. 2003 Aug 26;108(8):929-32
references: 12925451
references: Physiol Rev. 2007 Apr;87(2):425-56
references: 17429037
references: Circulation. 2008 Mar 18;117(11):1369-77
references: 18316490
references: Circ Res. 1997 Jul;81(1):110-9
references: 9201034
references: Cell Mol Life Sci. 2002 Sep;59(9):1561-8
references: 12440776
references: Cardiovasc Res. 2010 Feb 1;85(3):454-63
references: 19797425
references: J Am Coll Cardiol. 2005 Dec 20;46(12):2258-63
references: 16360055
references: J Mol Cell Cardiol. 2005 Mar;38(3):475-83
references: 15733907
references: Circulation. 2010 Apr 13;121(14):1606-13
references: 20351235
references: J Pharmacol Exp Ther. 2006 Jul;318(1):214-22
references: 16565163
references: Biophys J. 2006 Jan 1;90(1):77-91
references: 16214852
references: Circulation. 2009 Mar 10;119(9):1220-30
references: 19237662
references: Circulation. 1999 Jun 15;99(23):2993-3001
references: 10368116
references: J Pharmacol Exp Ther. 2004 Aug;310(2):599-605
references: 15031300
references: Nature. 1995 Aug 24;376(6542):683-5
references: 7651517
references: J Clin Invest. 2006 Dec;116(12):3127-38
references: 17124532
references: Circulation. 2002 May 28;105(21):2543-8
references: 12034663
references: Cell Mol Life Sci. 1998 Jun;54(6):597-605
references: 9676578
references: Circ Res. 2009 Jan 2;104(1):79-86
references: 19038865
references: Circ Res. 1996 Feb;78(2):262-73
references: 8575070
references: Circulation. 1999 Mar 30;99(12):1567-73
references: 10096932
references: Circ Arrhythm Electrophysiol. 2010 Feb;3(1):79-87
references: 20042767
references: J Cardiovasc Electrophysiol. 2006 May;17 Suppl 1:S169-S177
references: 16686675
references: Cardiovasc Res. 1999 May;42(2):270-83
references: 10533566
references: Circ Res. 2010 Oct 29;107(9):1150-61
references: 20814023
references: Life Sci. 2007 Sep 15;81(14):1152-9
references: 17884106
references: Circulation. 1997 Nov 18;96(10):3273-7
references: 9396415
references: Cardiovasc Res. 2003 Nov 1;60(2):404-12
references: 14613870
references: Circ Res. 1999 Apr 2;84(6):713-21
references: 10189359
references: Biophys J. 2007 Dec 1;93(11):3835-47
references: 17704163
references: Circulation. 2000 Dec 19;102(25):3053-9
references: 11120694
references: Circ Res. 1993 Aug;73(2):379-85
references: 8330380
references: Acta Pharmacol Sin. 2005 Jul;26(7):828-34
references: 15960889
references: Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1597-608
references: 18203851
references: Circ Cardiovasc Genet. 2010 Feb;3(1):78-87
references: 20160199
references: Circulation. 2002 Oct 1;106(14):1760-3
references: 12356626
references: Eur J Heart Fail. 2009 Aug;11(8):749-57
references: 19584134
references: Circ Res. 2006 Jul 21;99(2):172-82
references: 16778127