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

• DOI: 10.1161/circ.138.suppl_1.16677
• Publication Date: 2024-04-23T13:41:58Z
• Authors: Robert M Blanton; Hongwei Jin; Chris Madias; Yali Zhang; Bo Wang; Mark J Aronovitz; Daniel A Richards; Jonas B Galper
• Keywords: T wave alternans

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