The Role of Non-Glycolytic Glucose Metabolism in Myocardial Recovery Following Mechanical Unloading and Circulatory Support in Chronic Heart Failure

Abstract

Following left ventricular assist device (LVAD) mechanical unloading significant improvements in myocardial structure and function have been reported in some advanced heart failure (HF) patients, termed as Responders (R). Our prior work demonstrated a post-LVAD mismatch of glycolysis and oxidative phosphorylation characterized by upregulation of glycolysis without subsequent increase in pyruvate oxidation via the Krebs cycle. We hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, such as the pentose phosphate pathway (PPP) and one-carbon metabolism (OCM), which may mediate myocardial structural and functional improvement in Responders. We prospectively obtained myocardial tissue from Non-Failing Donor hearts (n=15) and from Responders (n=11) and Non-Responders (n=30) at LVAD implant (Pre-LVAD) and later at transplantation (Post-LVAD). Responders and Non-Responders were defined based on prior published criteria. We conducted protein expression and metabolite profiling and evaluated mitochondrial structure using electron microscopy. Western blot analysis of key PPP and OCM rate-limiting enzymes, glucose-6-phosphate dehydrogenase and phosphoglycerate dehydrogenase were significantly increased in Post-LVAD Responders (Post-R). In agreement with these findings the metabolite levels of these enzyme substrates such as sedoheptulose-6-phosphate (PPP) and serine and glycine (OCM) were decreased in Post-R. Furthermore, Post-R had significantly higher NADPH levels, reduced ROS levels, improved mitochondrial dynamics and enhanced glycosylation of the extracellular matrix (ECM) protein, α-dystroglycan, indicating increased flux of glucose into the PPP and OCM pathways and all together these findings correlated with the observed myocardial structural and functional improvement. The recovering human heart appears to direct glycolytic metabolites into the PPP and OCM pathways which could contribute to cardioprotection and improved myocardial function by generating NADPH to enhance biosynthesis for repair and by reducing oxidative stress.