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

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 I_NaP. Here, we report a mechanism for diabetes-induced QT prolongation that involves an increase in I_NaP 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 I_NaP that was reversed by activated PI3K or PIP3. The increases in APD and I_NaP 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 I_NaP 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 I_NaP. This mechanism may explain why the diabetic population has an increased risk of life-threatening arrhythmias.Patients with diabetes are at increased risk of developing life-threatening cardiac arrhythmias, independent of other risk factors such as atherosclerosis and hypertension. Diabetes is an independent risk factor for sudden cardiac death, mortality after myocardial infarction, and major complications of acute coronary syndrome such as ventricular arrhythmias (1). However, pathophysiological mechanisms responsible for the increased risk of sudden cardiac death remain poorly understood, and consequently there has been relatively little progress in the prevention and treatment of this diabetes complication. QT interval prolongation on the electrocardiogram (ECG) is a well-established risk factor for lethal ventricular arrhythmias (2), and not only do diabetic patients have a greater prevalence of QT interval prolongation than control populations (3,4), but a prolonged QT interval corrected for heart rate (QTc) is an independent risk factor for cardiovascular death in diabetic people (5–7).The signaling defect that causes QT interval prolongation in diabetes has remained elusive. An interesting lead came from our recent demonstration that decreased cardiac phosphoinositide 3-kinase (PI3K) signaling results in QT interval prolongation and is responsible for the increased risk of long QT syndrome and lethal arrhythmias caused by some anticancer drugs (8). Our results raised the possibility that suppression of this signaling pathway might also play a role in QT interval prolongation associated with diabetes, where reduced production of or sensitivity to insulin results in decreased activation of PI3K and its downstream effector, Akt.Primary prolongation of the QT interval (i.e., that which is independent of an altered QRS complex on the ECG) results from lengthening of the action potential duration (APD) in individual cardiac myocytes. The APD is regulated by inward and outward ion currents, and our previous study demonstrated that PI3K signaling regulates both types. PI3K inhibition caused reductions in the L-type calcium current (I_CaL), the delayed rectifier potassium currents I_Kr and I_Ks, and the peak sodium current (I_Na), whereas it caused an increase in the persistent (late) sodium current (I_NaP) (8). In the current study, we used mouse models to investigate a possible connection between decreased cardiac PI3K signaling and the prolonged QT interval in diabetes. Whereas I_Kr and I_Ks play little or no role in regulating the APD in adult mouse myocytes (9,10), I_NaP has a major role, such that expression of gain-of-function mutant sodium channels that increase I_NaP prolongs the murine APD and QT interval (11,12). Therefore, we used I_NaP as a marker of PI3K effects on cardiac ion channels and asked whether an increase in I_NaP contributes to QT interval prolongation in these diabetic mouse models.