Myocardial PKG1α dysregulation contributes to ventricular tachycardia pathogenesis in type 2 diabetes and metabolic syndrome.

BACKGROUND

Type 2 diabetes mellitus (DMII) and metabolic syndrome (MBS) increase ventricular arrhythmia and sudden cardiac death risk.

OBJECTIVE

This study aimed to identify mechanisms through which DMII and MBS promote ventricular tachycardia (VT).

METHODS

We performed programmed ventricular stimulation on leptin receptor mutant (Db/Db) mice with DMII; high-fat, high-sucrose (HFHS) diet-fed mice with MBS; and cyclic guanosine monophosphate (cGMP)-dependent protein kinase 1 alpha (PKG1α) leucine zipper mutant (LZM) mice, which have neither DMII nor MBS but have disrupted PKG1α signaling.

RESULTS

Programmed ventricular stimulation induced VT in Db/Db and HFHS diet-fed mice. Both models demonstrated autonomic dysfunction and decreased cGMP owing to decreased cardiac parasympathetic responsiveness. Conversely, cGMP augmentation with soluble guanylate cyclase stimulation (riociguat) or phosphodiesterase 5 inhibition (sildenafil) reduced VT inducibility. PKG1α LZM mice had normal autonomic responsiveness, but excess VT. Left ventricular tissue from HFHS diet-fed and LZM mice demonstrated hyperactivated glycogen synthase kinase-3 beta (GSK3β). GSK3β inhibition with TWS119 abolished inducible VT in all 3 models. Sarcoplasmic reticulum Ca2+ reuptake was delayed in cardiomyocytes (CMs) from all 3 models, reflected by increased time constant of cytoplasmic Ca2+ decline, tau. TWS119 reversed this effect. Phospholamban, which when unphosphorylated inhibits sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a-mediated Ca2+ reuptake from the cytosol, was hypophosphorylated in HFHS diet-fed and LZM mice, which was reversed by TWS119. CMs from HFHS diet-fed mice displayed increased frequency of early afterdepolarizations, further supporting Ca2+ dyshomeostasis. cGMP augmentation with riociguat/sildenafil prevented afterdepolarizations in HFHS CMs.

CONCLUSION

In DMII and MBS, reduced PKG1α signaling drives GSK3β hyperstimulation, calcium dyshomeostasis, and VT. Pharmacologic modulation of these pathways opposes VT pathogenesis.