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.

Calcium signaling in diabetic cardiomyocytes

“…However, while AP prolongation may help contractile function, it may be deleterious by triggering arrhythmias. In fact, the slower repolarization phase of the action potential may be responsible for the longer QRS and QT intervals observed in T1D animals and patients [18,[71][72][73].…”

Cardiac late Na+ current: Proarrhythmic effects, roles in long QT syndromes, and pathological relationship to CaMKII and oxidative stress

“…Recently, activation of phosphoinositide 3-kinase (PI3K) was shown to decrease I Na-L , whereas inhibition of this kinase was reported to increase I Na-L . 42 None of these kinases selectively target the Na þ channel; therefore, "druggable" targets to decrease I Na-L by modification of Na þ channel regulatory mechanisms are not apparent at present.…”

Inhibition of the α-Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic

“…In that study, we also showed that dofetilide inhibited the phosphorylation of Akt, a downstream target of PI3K, whereas moxifloxacin did not (Yang et al, 2014). QT intervals are prolonged in diabetes, and Lu et al have shown AP prolongation due to increased INaL in myocytes from mice models of diabetes (Lu et al, 2013).…”

“…Other work implicated the INaL effect in prolonging repolarization in animal models of diabetes (Lu et al, 2013), a clinical setting associated with increased QT intervals, and we have shown that some but not all drugs known to In order to determine which PI3K isoform(s) drive altered cardiac electrophysiology and arrhythmogenesis, in the present study we examined the effects of multiple PI3K inhibitors on cardiac action potentials (APs), late sodium current and other major repolarizing outward potassium currents in isolated adult mouse cardiomyocytes (which lack IKr and IKs) and transfected CHO cells. The experimental results are summarized here: (1) chronic (5 hours) exposure to PI3K-α subunit inhibitors (BYL716 and A66) and the Pan-PI3K blocker BKM-120 caused AP prolongation and abnormalities (EADs, DADs and triggered activity) and these effects were reversed when PIP3 was included in the pipette solution; (2) this chronic PI3K-α inhibitor exposure markedly increased late sodium current in mouse cardiomyocytes and in SCN5A-transfected cells, and the increased late current was abolished by ranolazine, a blocker of late sodium current; (3) chronic exposure to inhibitors of PI3K-β, -γ and -δ did not alter mouse cardiac APs or late INa; and (4) acute and chronic exposures to selective PI3K-α inhibitors did not affect two major repolarizing potassium currents (ITO and HERG).…”