Growing evidence implicates cardiac energetic metabolism in cardiac arrhythmogenesis. Here, we focused on the role of an alternative pathway of glycolysis, the hexosamines biosynthetic pathway (HBP). This pathway usually represents less than 5% of metabolic pathways, however it has been shown to be increased in some cardiomyopathies. HBP leads to the production of a glycosylation, consisting of the O-linked attachment of a single monosaccharide (N-acetyl-D-glucosamine, O-GlcNAc) to serine and threonine in nuclear and cytosolic proteins. This postranslational protein modification, like phosphorylation/dephosphorylation, may alter many processes, including protein activity & localisation.

To determine the role of HBP in cardiac physiopathology.

We studied the arrhythmogenesis of acute HBP overactivation by glucosamine administration (30min) on healthy working rat hearts perfused ex vivo. We performed cellular electrophysiology on left rat ventricular cells using the patch clamp technique. We also measured intracellular calcium transients and contraction using epi-fluorescence (Fura-2) and sarcomere shortening (Ionoptix, USA).

Glucosamine administration increases the probability of spontaneous arrhythmia events ex vivo, notably ventricular tachycardia, ventricular fibrillation and atrial fibrillation. Glucosamine perfusion in vitro significantly reduced action potential duration at 90% of repolarization. Glucosamine significantly increases the sustained repolarizing K+ current Isus with no significant modification of Ito or IK1. Furthermore, we observed a calcium transient modification by glucosamine perfusion, notably a significant increase of diastolic calcium and decrease of calcium transient amplitude.

Theses observations indicate that HBP participates in the regulation of cardiac electrical properties. To conclude, these data suggest a potential implication of HBP over-activation during arrhythmias.