Department of Cardiology (R.N., N.H.H., H.E., N.R.J., S.R., T.R.L., K.P., H.E.B., H.W.), Aarhus University Hospital, Aarhus, Denmark.
Department of Endocrinology and Metabolism (R.N., N.M.), Aarhus University Hospital, Aarhus, Denmark.
Circulation. 2019 Apr 30;139(18):2129-2141. doi: 10.1161/CIRCULATIONAHA.118.036459.
Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors' aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers.
Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO were evaluated using 11C-acetate positron emission tomography.
3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM ( P<0.001). CO rose by 2.0±0.2 L/min ( P<0.001) because of an increase in stroke volume of 20±2 mL ( P<0.001) and heart rate of 7±2 beats per minute (bpm) ( P<0.001). Left ventricular ejection fraction increased 8±1% ( P<0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM ( P<0.001). 3-OHB increased MVO without altering MEE. The response to 3-OHB infusion in terms of MEE and CO did not differ between HFrEF patents and age-matched volunteers.
3-OHB has beneficial hemodynamic effects in HFrEF patients without impairing MEE. These beneficial effects are detectable in the physiological concentration range of circulating 3-OHB levels. The hemodynamic effects of 3-OHB were observed in both HFrEF patients and age-matched volunteers. 3-OHB may potentially constitute a novel treatment principle in HFrEF patients.
心肌对 3-羟基丁酸（3-OHB）的利用在射血分数降低的心力衰竭（HFrEF）患者中增加。然而，这些患者循环血浆 3-OHB 水平升高的心血管影响尚不清楚。因此，作者的目的是调节 HFrEF 患者的循环 3-OHB 水平，并评估：（1）心输出量（CO）的变化；（2）3-OHB 水平与 CO 之间的潜在剂量反应关系；（3）对心肌外能量效率（MEE）和耗氧量（MVO）的影响；（4）心血管反应在 HFrEF 患者和年龄匹配的志愿者之间是否存在差异。
研究 1：16 例慢性 HFrEF 患者（左心室射血分数：37±3%）按交叉设计随机分为 3 小时 3-OHB 或安慰剂输注。患者通过 Swan-Ganz 导管和超声心动图进行侵入性监测。研究 2：在剂量反应研究中，8 例 HFrEF 患者在增加的 3-OHB 输注率下进行检查。研究 3 至 4：10 例 HFrEF 患者和 10 例年龄匹配的志愿者按交叉设计随机分为 3 小时 3-OHB 或安慰剂输注。使用 11C-乙酰酸盐正电子发射断层扫描评估 MEE 和 MVO。
3-OHB 输注使循环血浆 3-OHB 水平从 0.4±0.3 增加到 3.3±0.4 mM（P<0.001）。CO 增加 2.0±0.2 L/min（P<0.001），因为每搏量增加 20±2 mL（P<0.001）和心率增加 7±2 次/分钟（bpm）（P<0.001）。左心室射血分数增加 8±1%（P<0.001）。已经在血浆 3-OHB 水平为 0.7 mM 时观察到与 CO 显著增加 0.3 L/min 的剂量反应关系（P<0.001）。3-OHB 增加了 MVO，而不改变 MEE。HFrEF 患者和年龄匹配的志愿者之间在 3-OHB 输注后的 MEE 和 CO 反应没有差异。
3-OHB 在 HFrEF 患者中具有有益的血液动力学作用，而不会损害 MEE。这些有益作用在循环 3-OHB 水平的生理浓度范围内即可检测到。在 HFrEF 患者和年龄匹配的志愿者中均观察到 3-OHB 的血液动力学作用。3-OHB 可能是 HFrEF 患者的一种潜在治疗新方法。
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