The Role of Nonglycolytic Glucose Metabolism in Myocardial Recovery Upon Mechanical Unloading and Circulatory Support in Chronic Heart Failure

Abstract

Background: Significant improvements in myocardial structure and function have been reported in some advanced heart failure (HF) patients (termed Responders-R) following left ventricular assist device (LVAD)-induced mechanical unloading. This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Specifically, our prior work demonstrated a post-LVAD dissociation of glycolysis and oxidative-phosphorylation characterized by induction of glycolysis without subsequent increase in pyruvate oxidation via the TCA cycle. The underlying mechanisms responsible for this dissociation are not well understood. We hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, such as the pentose-phosphate pathway and one-carbon metabolism, which may mediate myocardial recovery in Responders. Methods: We prospectively obtained paired LV apical myocardial tissue from non-failing donor hearts as well as responders and non-responders at LVAD implant (Pre-LVAD) and transplantation (Post-LVAD). We conducted protein expression and metabolite profiling and evaluated mitochondrial structure using electron microscopy. Results: Western blot analysis shows significant increase in rate-limiting enzymes of pentose-phosphate pathway and one-carbon metabolism in Post-LVAD responders (Post-R) as compared to post-LVAD non-responders (Post-NR). The metabolite levels of these enzyme substrates, such as sedoheptulose-6-phosphate (pentose phosphate pathway) and serine and glycine (one-carbon metabolism) were also decreased in Post-R. Furthermore, Post-R had significantly higher NADPH levels, reduced ROS levels, improved mitochondrial density and enhanced glycosylation of the extracellular matrix protein, α-dystroglycan, all consistent with enhanced pentose-phosphate pathway and one-carbon metabolism that correlated with the observed myocardial recovery. Conclusions: The recovering heart appears to direct glycolytic metabolites into pentose-phosphate pathway and one-carbon metabolism which could contribute to cardioprotection by generating NADPH to enhance biosynthesis and by reducing oxidative stress. These findings provide further insights into mechanisms responsible for the beneficial impact of glycolysis induction during the recovery of failing human hearts following mechanical unloading.