Uncoupling of glycolysis from glucose oxidation accompanies the development of heart failure with preserved ejection fraction

作者：Natasha Fillmore, Jody Levasseur, Arata Fukushima, Cory S. Wagg, Wei Wang, Jason R.B. Dyck, Gary D. Lopaschuk · 发表于：Molecular Medicine · 年份：2018 · DOI：10.1186/s10020-018-0005-x · 被引用次数：130 · 研究领域：Cardiovascular Function and Risk Factors、Heart Failure Treatment and Management、Cardiovascular and exercise physiology

BACKGROUND: Alterations in cardiac energy metabolism contribute to the development and severity of heart failure (HF). In severe HF, overall mitochondrial oxidative metabolism is significantly decreased resulting in a reduced energy reserve. However, despite the high prevalence of HF with preserved ejection fraction (HFpEF) in our society, it is not clear what changes in cardiac energy metabolism occur in HFpEF, and whether alterations in energy metabolism contribute to the development of contractile dysfunction. METHODS: We directly assessed overall energy metabolism during the development of HFpEF in Dahl salt-sensitive rats fed a high salt diet (HSD) for 3, 6 and 9 weeks. RESULTS: Over the course of 9 weeks, the HSD caused a progressive decrease in diastolic function (assessed by echocardiography assessment of E'/A'). This was accompanied by a progressive increase in cardiac glycolysis rates (assessed in isolated working hearts obtained at 3, 6, and 9 weeks of HSD). In contrast, the subsequent oxidation of pyruvate from glycolysis (glucose oxidation) was not altered, resulting in an uncoupling of glucose metabolism and a significant increase in proton production. Increased glucose transporter (GLUT)1 expression accompanied this elevation in glycolysis. Decreases in cardiac fatty acid oxidation and overall adenosine triphosphate (ATP) production rates were not observed in early HF, but both significantly decreased as HF progressed to HF with reduced EF (i.e. 9 weeks of HSD)...