Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency
Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency
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DOI：
10.1093/cvr/cvz045
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发表时间：
2019-09-01
影响因子：
10.8
通讯作者：
Lopaschuk, Gary D.
中科院分区：
文献类型：
--
作者：
Ho, Kim L.;Zhang, Liyan;Lopaschuk, Gary D.
目的衰竭心脏由于能量代谢紊乱而能量匮乏，效率低下。虽然酮氧化在衰竭的心脏中有所增加，但这是否能提高心脏能量产生或效率仍不清楚。因此，我们评估了衰竭心脏的心脏代谢，并确定增加酮氧化是否能改善心脏能量产生和效率。方法和结果C57BL/6J小鼠采用假手术或横断主动脉缩窄术（TAC）诱导压力过载肥厚4周。从这些小鼠分离的工作心脏中灌注放射性标记的β -羟基丁酸酯（β OHB）、葡萄糖或棕榈酸酯，以评估心脏代谢。TAC小鼠的射血分数降低了45%。衰竭的心脏降低了葡萄糖氧化，而棕榈酸氧化保持不变，导致能量产生减少35%。β OHB水平从0.2 mM增加到0.6 mM，酮氧化率从251 +/- 24增加到834 +/- 116 nmol。G干wt（-1）。min(-1)，与假心脏相比，其速率显著增加，且糖酵解、葡萄糖或棕榈酸氧化速率均未降低。因此，酮类对TAC心脏能量产生的贡献增加到18%，总能量产生增加了23%。有趣的是，随着β OHB水平的增加，心脏中葡萄糖氧化和总ATP的产生也显著上调。然而，虽然总能量产生增加，但心脏效率没有提高。结论：增加衰竭心脏的酮氧化率会增加总能量产生，而不会影响葡萄糖或脂肪酸代谢，尽管不会提高心脏效率。
Aims The failing heart is energy-starved and inefficient due to perturbations in energy metabolism. Although ketone oxidation has been shown recently to increase in the failing heart, it remains unknown whether this improves cardiac energy production or efficiency. We therefore assessed cardiac metabolism in failing hearts and determined whether increasing ketone oxidation improves cardiac energy production and efficiency.Methods and results C57BL/6J mice underwent sham or transverse aortic constriction (TAC) surgery to induce pressure overload hypertrophy over 4-weeks. Isolated working hearts from these mice were perfused with radiolabelled beta-hydroxybutyrate (beta OHB), glucose, or palmitate to assess cardiac metabolism. Ejection fraction decreased by 45% in TAC mice. Failing hearts had decreased glucose oxidation while palmitate oxidation remained unchanged, resulting in a 35% decrease in energy production. Increasing beta OHB levels from 0.2 to 0.6 mM increased ketone oxidation rates from 251 +/- 24 to 834 +/- 116 nmol.g dry wt(-1) . min(-1) in TAC hearts, rates which were significantly increased compared to sham hearts and occurred without decreasing glycolysis, glucose, or palmitate oxidation rates. Therefore, the contribution of ketones to energy production in TAC hearts increased to 18% and total energy production increased by 23%. Interestingly, glucose oxidation, in parallel with total ATP production, was also significantly upregulated in hearts upon increasing beta OHB levels. However, while overall energy production increased, cardiac efficiency was not improved.Conclusions Increasing ketone oxidation rates in failing hearts increases overall energy production without compromising glucose or fatty acid metabolism, albeit without increasing cardiac efficiency.