title: Increased persistent sodium current due to decreased PI3K signaling contributes to QT prolongation in the diabetic heart.
abstract: Diabetes is an independent risk factor for sudden cardiac death and ventricular arrhythmia complications of acute coronary syndrome. Prolongation of the QT interval on the electrocardiogram is also a risk factor for arrhythmias and sudden death, and the increased prevalence of QT prolongation is an independent risk factor for cardiovascular death in diabetic patients. The pathophysiological mechanisms responsible for this lethal complication are poorly understood. Diabetes is associated with a reduction in phosphoinositide 3-kinase (PI3K) signaling, which regulates the action potential duration (APD) of individual myocytes and thus the QT interval by altering multiple ion currents, including the persistent sodium current INaP. Here, we report a mechanism for diabetes-induced QT prolongation that involves an increase in INaP caused by defective PI3K signaling. Cardiac myocytes of mice with type 1 or type 2 diabetes exhibited an increase in APD that was reversed by expression of constitutively active PI3K or intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate (PIP3), the second messenger produced by PI3K. The diabetic myocytes also showed an increase in INaP that was reversed by activated PI3K or PIP3. The increases in APD and INaP in myocytes translated into QT interval prolongation for both types of diabetic mice. The long QT interval of type 1 diabetic hearts was shortened by insulin treatment ex vivo, and this effect was blocked by a PI3K inhibitor. Treatment of both types of diabetic mouse hearts with an INaP blocker also shortened the QT interval. These results indicate that downregulation of cardiac PI3K signaling in diabetes prolongs the QT interval at least in part by causing an increase in INaP. This mechanism may explain why the diabetic population has an increased risk of life-threatening arrhythmias.
authors: Department of Physiology and Biophysics and the Institute for Molecular Cardiology, Stony Brook University, Stony Brook, New York.
authors: Zhongju
authors: Z
authors: Lu
authors: Ya-Ping
authors: YP
authors: Jiang
authors: Chia-Yen C
authors: CY
authors: Wu
authors: Lisa M
authors: LM
authors: Ballou
authors: Shengnan
authors: S
authors: Liu
authors: Eileen S
authors: ES
authors: Carpenter
authors: Michael R
authors: MR
authors: Rosen
authors: Ira S
authors: IS
authors: Cohen
authors: Richard Z
authors: RZ
authors: Lin
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000503:physiopathology; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D006329:Heart Conduction System / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D012964:Sodium / Q000502:physiology*
chemical_list: D012964:Sodium; D019869:Phosphatidylinositol 3-Kinases
references: Cardiovasc Res. 2004 Feb 1;61(2):256-67
references: 14736542
references: Am J Physiol Endocrinol Metab. 2005 May;288(5):E900-6
references: 15632103
references: J Physiol. 2001 Nov 15;537(Pt 1):83-92
references: 11711563
references: J Biol Chem. 2007 Aug 17;282(33):24463-70
references: 17562705
references: Diabetologia. 1999 Jan;42(1):68-75
references: 10027581
references: Diabetes. 2007 Nov;56(11):2780-9
references: 17666471
references: Diabet Med. 2001 Mar;18(3):199-205
references: 11318840
references: J Biol Chem. 2001 Nov 2;276(44):40910-6
references: 11533051
references: Pflugers Arch. 2012 Apr;463(5):649-68
references: 22415213
references: J Physiol. 2010 Dec 15;588(Pt 24):5015-32
references: 20974681
references: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2509-14
references: 9482916
references: Nat Med. 2001 Sep;7(9):1021-7
references: 11533705
references: Prog Biophys Mol Biol. 2008 Oct-Nov;98(2-3):230-7
references: 19041666
references: J Biol Chem. 2000 Feb 18;275(7):4803-9
references: 10671514
references: Circulation. 2012 Oct 30;126(18):2208-19
references: 23019294
references: J Physiol. 1993 Oct;470:411-29
references: 8308734
references: J Physiol. 2007 Jan 1;578(Pt 1):43-53
references: 17038432
references: Am J Physiol Heart Circ Physiol. 2006 May;290(5):H1763-9
references: 16327015
references: Am J Physiol. 1995 Oct;269(4 Pt 2):H1288-96
references: 7485560
references: Cardiovasc Res. 2007 Feb 1;73(3):512-20
references: 17182020
references: Am J Physiol. 1998 Mar;274(3):H747-51
references: 9530184
references: J Physiol. 2004 Mar 1;555(Pt 2):345-54
references: 14694146
references: Eur Heart J. 2007 Jan;28(1):88-136
references: 17220161
references: Sci Transl Med. 2012 Apr 25;4(131):131ra50
references: 22539774
references: Eur Heart J. 2010 Jan;31(1):100-11
references: 19797329
references: Diabetes. 2004 Feb;53(2):434-40
references: 14747295
references: Diabetes Care. 2000 Sep;23(9):1381-3
references: 10977037
references: Circulation. 1995 Dec 15;92(12):3381-6
references: 8521555
references: Cell Physiol Biochem. 2007;19(5-6):225-38
references: 17495463
references: Cardiovasc Res. 2012 Jan 1;93(1):12-23
references: 21937582
references: J Proteome Res. 2012 Dec 7;11(12):5994-6007
references: 23092124
references: Clin Endocrinol (Oxf). 2011 Jun;74(6):705-13
references: 21521253
references: J Mol Cell Cardiol. 1992 Aug;24(8):841-53
references: 1433314
references: J Cardiovasc Pharmacol. 2011 Oct;58(4):439-45
references: 21753738
references: Diabetes. 2006 Mar;55(3):608-15
references: 16505222
references: Circ Res. 1996 Jul;79(1):79-85
references: 8925572
references: Am J Physiol Heart Circ Physiol. 2010 Feb;298(2):H310-9
references: 19897715
references: J Intern Med. 2002 Apr;251(4):317-24
references: 11952882
references: Hum Mutat. 2009 Nov;30(11):1486-511
references: 19862833
references: Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1446-55
references: 16617123
references: Diabetes. 2004 Sep;53(9):2366-74
references: 15331547