Increased Persistent Sodium Current Due to Decreased PI3K Signaling Contributes to QT Prolongation in the Diabetic Heart

• Published in: Diabetes (New York, N.Y.) Vol. 62; no. 12; pp. 4257 - 4265
• Main Authors: ZHONGJU LU, JIANG, Ya-Ping, WU, Chia-Yen C, BALLOU, Lisa M, SHENGNAN LIU, CARPENTER, Eileen S, ROSEN, Michael R, COHEN, Ira S, LIN, Richard Z
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2013
• Subjects: Action Potentials - physiology; Animals; Arrhythmia; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - physiopathology; Biological and medical sciences; Brugada Syndrome; Cardiac arrhythmia; Cardiac Conduction System Disease; Cardiac dysrhythmias; Cardiology. Vascular system; Cellular signal transduction; Complications and side effects; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - physiopathology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genetic aspects; Heart; Heart Conduction System - abnormalities; Heart Conduction System - metabolism; Heart Conduction System - physiopathology; Medical sciences; Mice; Myocytes, Cardiac - metabolism; Original Research; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Physiological aspects; Risk factors; Rodents; Sodium; Sodium - physiology; United States; Endocrinopathy; Heart; Arrhythmia; Diabetes mellitus; Prolonged QT interval; Cardiovascular disease; Ionic current; Conduction disorder; Signal transduction; Sodium; Heart block; Heart disease; Circulatory system
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db13-0420

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.