Abstract 16677: Protein Kinase G I Alpha Attenuates Inducible Ventricular Tachycardia and QRS/T Wave Alternans in the Type II Diabetic Heart

Abstract

Introduction: Diabetes increases ventricular tachycardia (VT) and sudden cardiac death risk in humans. We previously found the type I diabetic (DMI) heart displays: reduced responsiveness to parasympathetic stimulation; increased QRS/T Wave alternans (marker of proarrhythmic calcium dyshomeostasis); and hyperactive GSK3beta. Cardiac parasympathetic stimulation promotes production of intracellular cyclic GMP (cGMP). The effects of cGMP and its downstream effector PKG, on these indices of VT in type II diabetes (DMII) remain poorly understood. Hypothesis: PKGIa modulates inducibility of VT and QRS/TWA in the DMII heart and mediates the cGMP effect on VT through inhibition of myocardial GSK3beta. Methods: Using an established protocol of programmed ventricular stimulation we measured: VT incidence, duration, and QRS/T Wave alternans. We studied the following mice: wild type; Db/Db model of DMII; high fat high sucrose (HFHS) model of insulin resistance; and the PKGIa leucine zipper mutant (LZM) mouse, which has no DM but has PKGIa disrupting mutations. Mice were treated with or without the cGMP-augmenting phosphodiesterase inhibitor sildenafil 10 mg/kg, or the GSK3b inhibitor TWS119 20 mg/kg. Results: LVs of HFHS mice displayed 30 ± 8% reduction of cGMP compared with control (p<0.05, n=3 per group), while myocardial cGMP in LZM mice did not differ from control. In failing LVs from humans, there was also a 46% reduction in myocardial cGMP in DM compared with nondiabetic (p= .058, n=3 per group). Db/Db and HFHS mice had increased inducible VT (0.25 +/- 0.1 s in Db/Db, 2.2 +/- 1 s HFHS, vs 0 s in WT control, p <0.05), as well as TWA. Treatment with sildenafil reduced VT incidence, duration, and TWA in Db/Db and HFHS mice. LZM mice also had increased VT duration and TWA incidence (0 of 4 in WT vs 5 of 6 in LZM, p<0.05). Inhibition of GSK3β rescued inducibility of VT in Db/Db, HFHS, and in LZM mice. Conclusions: These findings support that in the DMII heart reduced cGMP promotes VT, whereas pharmacological augmentation of cGMP inhibits VT. Inducible VT and TWA in the PKG LZM mouse provides direct support that PKGIa opposes VT in the DMII heart. These support that cGMP activation of PKG inhibits GSK3beta, leading to reduced incidence of inducible VT.