BACKGROUND:Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction.METHODS:In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right-sided heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents.RESULTS:We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1–0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, −2 mm Hg [95% CI, −4 to −1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (−3 mm Hg [95% CI, −5 to −1] ) and higher mean CO (0.5 L/min [95% CI, 0.1–0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, −98 ng/L [95% CI, −185 to −23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes.CONCLUSIONS:KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650.

中文翻译：

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口服酮酯治疗对射血分数降低的心力衰竭患者的心血管作用：一项随机、对照、双盲试验

背景：心力衰竭引发心肌代谢底物利用的转变，有利于酮体3-羟基丁酸作为能量来源。我们假设，14 天的酮酯 (KE) 治疗将改善射血分数降低的心力衰竭患者的静息和运动血流动力学以及运动能力。 方法：在一项随机、双盲交叉研究中，患有心脏病的非糖尿病患者射血分数降低的失败者接受 14 天 KE 和 14 天等热量非 KE 比较方案，每天 4 剂，间隔 14 天的清除期。每个治疗期后，参与者接受右侧心导管检查、超声心动图检查，并在血浆谷水平和给药后进行血液采样。参与者在第二次给药后接受了运动血流动力学评估。主要终点是静息心输出量（CO）。次要终点包括静息和运动时肺毛细血管楔压、峰值运动 CO 和代谢当量。 结果：我们纳入了 24 名射血分数降低的心力衰竭患者（17 名男性；65±9 岁；均为白人）。与等热量比较者相比，KE 后的静息 CO 谷值更高（5.2±1.1 L/min 与 5.0±1.1 L/min；差异为 0.3 L/min [95% CI，0.1–0.5），肺毛细血管楔压为较低（8±3 mm Hg 与 11±3 mm Hg；差异，−2 mm Hg [95% CI，−4 至 −1]）。这些变化在 KE 给药后被放大。在所有运动强度中，KE 治疗与较低的平均运动肺毛细血管楔压（−3 mm Hg [95% CI，-5 至 -1]）和较高的平均 CO（0.5 L/min [95% CI，0.1– 0.8]），在低至中度稳态运动时有显着差异，但在峰值时没有显着差异。治疗之间的代谢当量保持相似。在探索性分析中，KE 治疗与 NT-proBNP（N 端 B 型利钠肽原；差异，−98 ng/L [95% CI，−185 至 −23]）降低 18%、左心室升高相关。射血分数（37±5 对比 34±5%；P = 0.01），以及较低的左心房和心室容积。 结论：14 天的 KE 治疗与静息时较高的 CO 和较低的充盈压、心脏容积和 NT- 相关。 proBNP 水平与等热量比较物进行比较。这些变化在运动过程中持续存在，并且是在最佳药物治疗的基础上实现的。持续调节循环酮体是射血分数降低的心力衰竭患者的潜在治疗原则。注册：URL：https://www.clinicaltrials.gov；唯一标识符：NCT05161650。