Department of Cardiology, Aarhus University Hospital, Denmark (N.G., K.B.-H., K.H.C., B.T.L., S.H.P., M.J.A., R.N., H.W.).
Department of Clinical Medicine (N.G., K.B.-H., K.H.C., B.T.L., S.H.P., M.J.A., R.N., N.M., H.W.), Aarhus University, Denmark.
Circulation. 2024 Nov 12;150(20):1570-1583. doi: 10.1161/CIRCULATIONAHA.124.069732. Epub 2024 Aug 20.
Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2D). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2D with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2D and HFpEF remain unknown.
A total of 24 patients with T2D and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period.
During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; <0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs.
In patients with T2D and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2D and HFpEF.
URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.
射血分数保留的心力衰竭（HFpEF）是 2 型糖尿病（T2D）患者发病率和死亡率的主要原因。在没有 T2D 的慢性射血分数降低的心力衰竭患者中，循环中酮体 3-羟基丁酸水平的急性升高对急性血流动力学具有有益的影响。然而，T2D 和 HFpEF 患者长期口服酮酯（KE）治疗的心血管效应仍不清楚。
共有 24 名 T2D 和 HFpEF 患者完成了一项为期 6 周的随机、双盲交叉研究。所有患者均接受 2 周 KE 治疗（25 g D-β-羟基丁酸-（R）-1,3-丁二醇×4 次/d）和等热量等容安慰剂，间隔 2 周洗脱期。在每个治疗期结束时，患者在干预的谷底水平接受右心导管检查、超声心动图和血液样本检测，然后在单次剂量后 4 小时休息期进行检测。随后给予第二次剂量，然后进行运动试验。主要终点是 4 小时休息期间的心输出量。
在 4 小时的休息期间，KE 治疗后的循环 3-羟基丁酸水平比安慰剂高 10 倍（1010±56 µmol/L；<0.001）。与安慰剂相比，KE 治疗在 4 小时期间使心输出量增加 0.2 L/min（95%CI，0.1 至 0.3），并使休息时肺毛细血管楔压降低 1 mmHg（95%CI，-2 至 0），运动峰值时降低 5 mmHg（95%CI，-9 至 -1）。KE 治疗在运动期间显著降低了压力-流量关系（△肺毛细血管楔压/△心输出量）（<0.001），并使运动峰值时的每搏量增加 10 mL（95%CI，0 至 20）。KE 治疗还使左心室舒张末期压力-容积关系右移，提示左心室僵硬度降低，顺应性改善。在接受钠-葡萄糖共转运蛋白-2 抑制剂和胰高血糖素样肽-1 类似物治疗的患者中，KE 治疗也观察到有利的血液动力学反应。
在 T2D 和 HFpEF 患者中，口服 KE 治疗 2 周可增加心输出量，降低心脏充盈压和心室僵硬度。在运动峰值时，KE 治疗可显著降低肺毛细血管楔压并改善压力-流量关系。循环酮体水平的调节可能是 T2D 和 HFpEF 患者的一种潜在新治疗方法。
