Sun Qiuyu, Wagg Cory S, Wong Nathan, Wei Kaleigh, Ketema Ezra B, Zhang Liyan, Fang Liye, Seubert John M, Lopaschuk Gary D
Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
ESC Heart Fail. 2025 May 26;12(4):3179-82. doi: 10.1002/ehf2.15319.
Cardiac energy metabolism is disrupted in heart failure with preserved ejection fraction (HFpEF), as characterized by a switch from glucose oxidation towards fatty acid oxidation. However, although oxidation of ketones is an important source of ATP it remains unclear how the heart oxidizes ketones in HFpEF. It is also unclear whether elevating ketone supply to the heart can improve cardiac energetics and/or provide functional benefit for the hearts in HFpEF.
The present study investigated the effects of increasing ketone supply to the heart via ketone supplementation or SGLT2 inhibitor treatment in a mouse model of HFpEF.
HFpEF was induced in 13-month-old C57BL/6N female mice with 60% high-fat diet and L-NAME (0.5 g/L/day in the drinking water) for 6 weeks. In parallel, two other groups of mice were maintained on the HFpEF protocol while also receiving either a ketone ester supplement (1-3 butanediol 1 g/kg/day) or SGLT2 inhibitor (empagliflozin 10 mg/kg/day) for 6 weeks. Control mice were fed with regular low-fat diet and regular drinking water. Hearts of the mice were excised and perfused in the isolated working mode aerobically with 5-mM glucose, 0.8-mM palmitate, 100-μU/mL insulin, with either low (0.6 mM) or high (1 mM) levels of β-hydroxybutyrate. Metabolic rates of the hearts were measured with radiolabelled [U-C] glucose, [9,10-H] palmitate and [3-C] β-hydroxybutyrate.
In HFpEF mouse hearts, glucose oxidation was significantly decreased with a parallel increase in fatty acid oxidation. Increasing β-hydroxybutyrate levels from 0.6 to 1 mM in the perfusate resulted in a rise in ketone oxidation rates in control hearts (from 861 ± 63 to 1377 ± 94 nmol g dry wt min), which was muted in HFpEF hearts (from 737 ± 68 to 897 ± 134 nmol g dry wt min). Following ketone ester supplement or SGLT2 inhibitor treatment, HFpEF mice presented with restored ketone oxidation rates (from 674 ± 36 to 1181 ± 115 nmol g dry wt min with ketone ester supplement and from 797 ± 121 to 1240 ± 120 nmol g dry wt min with SGLT2i). Yet, this was not associated with improvement in cardiac function.
In HFpEF mice, the heart switches from glucose oxidation to fatty acid oxidation, with ketone oxidation being impaired. Increasing ketone supply to the heart via ketone ester supplementation or SGLT2 inhibitor treatment increases myocardial ketone oxidation rates but was not associated with functional improvements. Unlike HFrEF, ketone supplementation strategies may be less effective in HFpEF due to an impairment of myocardial ketone oxidation in HFpEF.
射血分数保留的心力衰竭（HFpEF）患者存在心脏能量代谢紊乱，其特征是从葡萄糖氧化转向脂肪酸氧化。然而，尽管酮体氧化是三磷酸腺苷（ATP）的重要来源，但目前尚不清楚HFpEF患者心脏中酮体是如何氧化的。此外，增加心脏酮体供应是否能改善心脏能量代谢和/或对HFpEF患者的心脏产生功能益处也尚不明确。
本研究在HFpEF小鼠模型中，探究通过补充酮体或使用钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂增加心脏酮体供应的效果。
对13月龄C57BL/6N雌性小鼠采用60%高脂饮食并给予L-硝基精氨酸甲酯（L-NAME，饮用水中浓度为0.5 g/L/天）6周，诱导建立HFpEF模型。同时，另外两组小鼠按照HFpEF造模方案饲养，在此期间分别给予酮酯补充剂（1,3-丁二醇1 g/kg/天）或SGLT2抑制剂（恩格列净10 mg/kg/天），持续6周。对照小鼠给予常规低脂饮食和普通饮用水。切除小鼠心脏，在离体工作模式下进行有氧灌注，灌注液含有5 mM葡萄糖、0.8 mM棕榈酸、100 μU/mL胰岛素，以及低水平（0.6 mM）或高水平（1 mM）的β-羟基丁酸。使用放射性标记的[U-C]葡萄糖、[9,10-H]棕榈酸和[3-C]β-羟基丁酸测量心脏的代谢率。
在HFpEF小鼠心脏中，葡萄糖氧化显著降低，脂肪酸氧化相应增加。灌注液中β-羟基丁酸水平从0.6 mM增加到1 mM时，对照心脏的酮体氧化率升高（从861±63增加到1377±94 nmol/g干重/分钟），而HFpEF心脏中的升高幅度较小（从737±68增加到897±134 nmol/g干重/分钟）。给予酮酯补充剂或SGLT2抑制剂治疗后，HFpEF小鼠的酮体氧化率恢复（酮酯补充剂组从674±36增加到1181±115 nmol/g干重/分钟，SGLT2抑制剂组从797±121增加到1240±120 nmol/g干重/分钟）。然而，这并未伴随心脏功能的改善。
在HFpEF小鼠中，心脏从葡萄糖氧化转向脂肪酸氧化，酮体氧化受损。通过补充酮酯或使用SGLT2抑制剂增加心脏酮体供应可提高心肌酮体氧化率，但与功能改善无关。与射血分数降低的心力衰竭（HFrEF）不同，由于HFpEF心肌酮体氧化受损，补充酮体策略在HFpEF中可能效果较差。
