Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Cardiovasc Res. 2024 Sep 2;120(10):1126-1137. doi: 10.1093/cvr/cvae092.
Cardiac energy metabolism is perturbed in ischaemic 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.
C57BL/6J male mice underwent either a sham surgery or permanent left anterior descending 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 β-hydroxybutyrate (β-OHB) (0.6 mM) to assess mitochondrial oxidative metabolism and glycolysis. 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.
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 ischaemic heart and a decrease in insulin-stimulated glucose oxidation.
在缺血性心力衰竭中，心脏能量代谢受到干扰，其特征是从线粒体氧化代谢向糖酵解转移。值得注意的是，衰竭的心脏比健康的心脏更依赖酮体供能，这是一种适应性机制，可以改善衰竭心脏的能量匮乏状态。然而，这种机制是否可以在治疗中得到应用尚不清楚。因此，我们的目的是确定通过生酮饮食增加心脏酮体供应是否可以改善心力衰竭的预后。
C57BL/6J 雄性小鼠接受假手术或永久性左前降支冠状动脉结扎手术，以诱导心力衰竭。2 周后，小鼠再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检查，以评估体内心脏功能和结构。最后，从这些小鼠中分离出工作心脏，并用适当的 3H 或 14C 标记的葡萄糖（5mM）、棕榈酸（0.8mM）和β-羟丁酸（β-OHB）（0.6mM）灌注，以评估线粒体氧化代谢和糖酵解。心力衰竭小鼠的射血分数下降了 56%，而生酮饮食喂养并不能改善这一情况。有趣的是，生酮饮食喂养的小鼠心脏葡萄糖氧化率明显下降。尽管血液酮体水平升高，但心脏酮体氧化率并没有增加，这可能是由于关键酮体氧化酶的表达降低所致。此外，在生酮饮食的小鼠中，没有观察到整体心脏能量产生的增加，而是观察到对脂肪酸氧化作为心脏能量产生来源的依赖增加。这导致心力衰竭小鼠在生酮饮食喂养后心脏效率降低。
我们的结论是，生酮饮食不能改善衰竭心脏的心脏功能，这是由于生酮饮食诱导的缺血性心脏中脂肪酸氧化过度和胰岛素刺激的葡萄糖氧化减少所致。
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