Aims Cardiac energy metabolism is perturbed in ischemic heart failure and is characterized by a shift from mitochondrial oxidative metabolism to glycolysis. Notably, the failing heart relies more on ketones for energy than a healthy heart, an adaptive mechanism that improves the energy-starved status of the failing heart. However, whether this can be implemented therapeutically remains unknown. Therefore, our aim was to determine if increasing ketone delivery to the heart via a ketogenic diet can improve the outcomes of heart failure. Methods C57BL/6J male mice underwent either a sham surgery or permanent left anterior descending (LAD) coronary artery ligation surgery to induce heart failure. After 2 weeks, mice were then treated with either a control diet or a ketogenic diet for 3 weeks. Transthoracic echocardiography was then carried out to assess in vivo cardiac function and structure. Finally, isolated working hearts from these mice were perfused with appropriately 3H or 14C labelled glucose (5 mM), palmitate (0.8 mM), and ß-hydroxybutyrate (0.6 mM) to assess mitochondrial oxidative metabolism and glycolysis. Results Mice with heart failure exhibited a 56% drop in ejection fraction which was not improved with a ketogenic diet feeding. Interestingly, mice fed a ketogenic diet had marked decreases in cardiac glucose oxidation rates. Despite increasing blood ketone levels, cardiac ketone oxidation rates did not increase, probably due to a decreased expression of key ketone oxidation enzymes. Furthermore, in mice on the ketogenic diet no increase in overall cardiac energy production was observed, and instead there was a shift to an increased reliance on fatty acid oxidation as a source of cardiac energy production. This resulted in a decrease in cardiac efficiency in heart failure mice fed a ketogenic diet. Conclusions We conclude that the ketogenic diet does not improve heart function in failing hearts, due to ketogenic diet-induced excessive fatty acid oxidation in the ischemic heart and a decrease in insulin-stimulated glucose oxidation.

中文翻译：

---

生酮饮食不能改善缺血性心力衰竭的心脏功能并减弱葡萄糖氧化

目的 缺血性心力衰竭时心脏能量代谢受到干扰，其特征是从线粒体氧化代谢转变为糖酵解。值得注意的是，衰竭的心脏比健康的心脏更依赖酮来获取能量，这是一种改善衰竭心脏能量匮乏状态的适应性机制。然而，这是否可以在治疗上实施仍然未知。因此，我们的目的是确定通过生酮饮食增加向心脏的酮输送是否可以改善心力衰竭的结果。方法 C57BL/6J 雄性小鼠接受假手术或永久性左前降支 (LAD) 冠状动脉结扎手术以诱导心力衰竭。 2周后，小鼠接受对照饮食或生酮饮食治疗3周。然后进行经胸超声心动图以评估体内心脏功能和结构。最后，用适当的 3H 或 14C 标记的葡萄糖 (5 mM)、棕榈酸盐 (0.8 mM) 和 β-羟基丁酸盐 (0.6 mM) 灌注这些小鼠的分离工作心脏，以评估线粒体氧化代谢和糖酵解。结果患有心力衰竭的小鼠的射血分数下降了 56%，而生酮饮食喂养并没有改善这一情况。有趣的是，喂食生酮饮食的小鼠心脏葡萄糖氧化率显着降低。尽管血酮水平增加，但心脏酮氧化率并未增加，可能是由于关键酮氧化酶的表达减少。此外，在生酮饮食的小鼠中，没有观察到总体心脏能量产生的增加，相反，对脂肪酸氧化作为心脏能量产生来源的依赖增加。这导致喂食生酮饮食的心力衰竭小鼠的心脏效率下降。结论 我们得出的结论是，生酮饮食不能改善衰竭心脏的心脏功能，因为生酮饮食诱导缺血性心脏中脂肪酸过度氧化，并且胰岛素刺激的葡萄糖氧化减少。