title: New antiarrhythmic targets to control intracellular calcium handling.
abstract: Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.
authors.affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM, Utrecht, the Netherlands, h.e.driessen@gmail.com.
authors.forename: H E
authors.initials: HE
authors.lastname: Driessen
authors.forename: V J A
authors.initials: VJ
authors.lastname: Bourgonje
authors.forename: T A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: M A
authors.initials: MA
authors.lastname: Vos
references.citation: Curr Drug Targets. 2011 May;12(5):709-23
references.pmid: 21291389
references.citation: Pharmacol Ther. 2005 Apr;106(1):39-55
references.pmid: 15781121
references.citation: J Pharmacol Exp Ther. 2013 Jan;344(1):23-32
references.pmid: 23010360
references.citation: Br J Pharmacol. 2002 Mar;135(5):1096-100
references.pmid: 11877314
references.citation: J Mol Cell Cardiol. 2011 Dec;51(6):936-44
references.pmid: 21888910
references.citation: Proc Natl Acad Sci U S A. 1986 Dec;83(24):9497-501
references.pmid: 3467320
references.citation: Neurochem Int. 1996 Apr;28(4):343-58
references.pmid: 8740440
references.citation: Nature. 1986 Feb 13-19;319(6054):597-9
references.pmid: 2418367
references.citation: J Cardiovasc Pharmacol. 2012 Oct;60(4):357-66
references.pmid: 23064241
references.citation: Heart Rhythm. 2013 Apr;10(4):592-9
references.pmid: 23246599
references.citation: Basic Res Cardiol. 2000;95 Suppl 1:I25-30
references.pmid: 11192348
references.citation: J Pharmacol Exp Ther. 2001 Jul;298(1):249-56
references.pmid: 11408549
references.citation: Nat Med. 2011 Jul 10;17(8):1003-9
references.pmid: 21743453
references.citation: J Pharmacol Exp Ther. 2006 Jul;318(1):214-22
references.pmid: 16565163
references.citation: Heart. 2006 Jul;92 Suppl 4:iv1-iv5
references.pmid: 16775091
references.citation: Zhonghua Xin Xue Guan Bing Za Zhi. 2005 Apr;33(4):364-8
references.pmid: 15932674
references.citation: Blood Vessels. 1978;15(1-3):55-64
references.pmid: 204383
references.citation: J Cardiovasc Pharmacol. 2004 Aug;44(2):192-9
references.pmid: 15243300
references.citation: Jpn J Pharmacol. 1999 Mar;79(3):275-81
references.pmid: 10230854
references.citation: J Pharmacol Exp Ther. 2004 Aug;310(2):599-605
references.pmid: 15031300
references.citation: J Clin Invest. 2009 May;119(5):1082-5
references.pmid: 19422097
references.citation: Ann N Y Acad Sci. 2007 Mar;1099:339-48
references.pmid: 17446474
references.citation: Heart Rhythm. 2008 Oct;5(10):1444-52
references.pmid: 18929333
references.citation: Nat Med. 2009 Apr;15(4):380-3
references.pmid: 19330009
references.citation: Circ Res. 2008 Jun 6;102(11):1398-405
references.pmid: 18451338
references.citation: J Cardiovasc Electrophysiol. 2003 Aug;14(8):880-4
references.pmid: 12890053
references.citation: Am J Physiol Heart Circ Physiol. 2011 Sep;301(3):H921-35
references.pmid: 21666112
references.citation: J Electrocardiol. 2007 Nov-Dec;40(6 Suppl):S8-14
references.pmid: 17993335
references.citation: Trends Cardiovasc Med. 2004 Feb;14(2):61-6
references.pmid: 15030791
references.citation: Pharmacol Ther. 2011 Aug;131(2):204-20
references.pmid: 21414358
references.citation: Eur J Pharmacol. 2005 Jan 4;506(3):249-55
references.pmid: 15627435
references.citation: N Engl J Med. 2001 Nov 15;345(20):1473-82
references.pmid: 11794197
references.citation: J Huazhong Univ Sci Technolog Med Sci. 2012 Aug;32(4):485-489
references.pmid: 22886958
references.citation: Br J Pharmacol. 2000 Dec;131(7):1363-72
references.pmid: 11090108
references.citation: J Cardiovasc Pharmacol Ther. 2013 Mar;18(2):184-90
references.pmid: 23144205
references.citation: J Physiol. 2006 Jul 15;574(Pt 2):509-18
references.pmid: 16627565
references.citation: Circ Res. 1992 Nov;71(5):1231-41
references.pmid: 1327577
references.citation: Br J Pharmacol. 2004 Dec;143(7):827-31
references.pmid: 15504749
references.citation: Br J Pharmacol. 2008 Mar;153(5):915-25
references.pmid: 17994112
references.citation: Biochim Biophys Acta. 2013 Dec;1832(12):2425-31
references.pmid: 23770282
references.citation: Eur J Pharmacol. 2007 Jan 19;555(1):54-60
references.pmid: 17112502
references.citation: Circulation. 2002 Feb 12;105(6):770-4
references.pmid: 11839636
references.citation: Circulation. 2004 Aug 24;110(8):904-10
references.pmid: 15302796
references.citation: J Pharmacol Exp Ther. 2006 Apr;317(1):292-9
references.pmid: 16368898
references.citation: J Cardiovasc Electrophysiol. 2006 May;17 Suppl 1:S169-S177
references.pmid: 16686675
references.citation: Circ Res. 2006 Aug 4;99(3):292-8
references.pmid: 16825580
references.citation: J Mol Cell Cardiol. 2010 Jan;48(1):76-82
references.pmid: 19729017
references.citation: Expert Opin Drug Saf. 2009 May;8(3):345-55
references.pmid: 19432556
references.citation: Circ Arrhythm Electrophysiol. 2013 Apr;6(2):371-9
references.pmid: 23515266
references.citation: J Pharmacol Sci. 2007 Feb;103(2):241-6
references.pmid: 17310075
references.citation: J Physiol. 1976 Dec;263(2):73-100
references.pmid: 1018270
references.citation: Heart Rhythm. 2013 Jul;10(7):1036-43
references.pmid: 23524321
references.citation: Am J Physiol Heart Circ Physiol. 2012 Jun 1;302(11):H2331-40
references.pmid: 22467308
references.citation: Pharmacol Ther. 2012 Apr;134(1):26-42
references.pmid: 22197992
references.citation: Prog Cardiovasc Dis. 2008 May-Jun;50(6):439-48
references.pmid: 18474286
references.citation: J Pharmacol Exp Ther. 2004 Jul;310(1):83-9
references.pmid: 15028781
references.citation: Am J Physiol Heart Circ Physiol. 2011 Jul;301(1):H180-91
references.pmid: 21478408
references.citation: Adv Pharmacol. 2010;59:1-30
references.pmid: 20933197
references.citation: Circulation. 2007 Oct 9;116(15):1647-52
references.pmid: 17804441
references.citation: Acta Pharmacol Sin. 2011 Mar;32(3):311-20
references.pmid: 21258356
references.citation: J Mol Cell Cardiol. 2006 Dec;41(6):1031-8
references.pmid: 17027025
references.citation: Circ Heart Fail. 2009 Nov;2(6):664-75
references.pmid: 19919992
references.citation: Heart Rhythm. 2012 Nov;9(11):1875-83
references.pmid: 22846339
references.citation: Pacing Clin Electrophysiol. 2006 Mar;29(3):290-5
references.pmid: 16606397
references.citation: Basic Res Cardiol. 2011 Mar;106(2):263-72
references.pmid: 21174213
references.citation: J Mol Cell Cardiol. 2011 Jan;50(1):214-22
references.pmid: 20937285
references.citation: J Mol Cell Cardiol. 2004 May;36(5):691-700
references.pmid: 15135664
references.citation: Circulation. 2006 Sep 5;114(10):e385-484
references.pmid: 16935995
references.citation: Circulation. 2011 Jul 19;124(3):304-13
references.pmid: 21709064
references.citation: J Am Coll Cardiol. 2010 Feb 23;55(8):801-9
references.pmid: 20170820
references.citation: Circ Res. 2011 Sep 2;109(6):712-3
references.pmid: 21885838
references.citation: Biochem Biophys Res Commun. 1991 Dec 31;181(3):968-75
references.pmid: 1662507
references.citation: Br J Pharmacol. 2009 Mar;156(6):920-32
references.pmid: 19222480
references.citation: Cardiovasc Res. 2004 Aug 15;63(3):476-86
references.pmid: 15276473
references.citation: J Biol Chem. 2012 Mar 9;287(11):8495-506
references.pmid: 22253441
references.citation: J Physiol. 1997 May 15;501 ( Pt 1):3-16
references.pmid: 9174989
references.citation: Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1636-44
references.pmid: 22307670
references.citation: J Pharmacol Exp Ther. 1998 Dec;287(3):996-1006
references.pmid: 9864285
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2000 Jun;361(6):646-53
references.pmid: 10882040
references.citation: Cardiovasc Res. 2007 Nov 1;76(2):236-46
references.pmid: 17644079
references.citation: Circ Res. 2006 Aug 18;99(4):398-406
references.pmid: 16840718
references.citation: Nature. 2002 Jan 10;415(6868):198-205
references.pmid: 11805843
references.citation: J Am Coll Cardiol. 2011 Jan 18;57(3):366-75
references.pmid: 21232675
references.citation: Science. 2004 Apr 9;304(5668):292-6
references.pmid: 15073377
references.citation: Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1923-9
references.pmid: 19767532
references.citation: Circulation. 2012 Mar 27;125(12):1563-76
references.pmid: 22451606
references.citation: Eur J Pharmacol. 2011 Dec 15;672(1-3):126-34
references.pmid: 22001562
references.citation: Cardiovasc Res. 2010 Jul 1;87(1):50-9
references.pmid: 20080988
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2005 Jul;372(1):63-70
references.pmid: 16086157
references.citation: J Biol Chem. 2002 Jan 11;277(2):1261-7
references.pmid: 11694533
references.citation: Circulation. 1999 Dec 14;100(24):2437-42
references.pmid: 10595957
references.citation: Cardiovasc Res. 2000 Jun;46(3):376-92
references.pmid: 10912449
references.citation: Ann N Y Acad Sci. 2008 Mar;1123:113-8
references.pmid: 18375583