Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients
Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients
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DOI：
10.1161/circulationaha.118.036459
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发表时间：
2019-04-30
期刊：
影响因子：
37.8
通讯作者：
Wiggers, Henrik
中科院分区：
文献类型：
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作者：
Nielsen, Roni;Moller, Niels;Wiggers, Henrik
背景：心力衰竭和射血分数降低（HFREF）患者的3-羟基丁酸（3-OHB）的心肌利用率增加。但是，这些患者循环血浆-3-OHB水平增加的心血管效应尚不清楚。因此，作者的目的是调节HFREF患者循环3-OHB水平并评估：（1）心输出量的变化（CO）； （2）3-OHB水平与CO之间的潜在剂量响应关系； （3）对心肌外部能量效率（MEE）和氧气消耗的影响（MVO 2）； （4）HFREF患者和年龄匹配的志愿者的心血管反应是否有所不同。方法：研究1：16例慢性HFREF患者（左心室射血分数：37 +/- 3％）在跨界设计中随机分配至3-OHB或安慰剂输注3小时。用天鹅导管和超声心动图对患者进行侵入性监测。研究2：在一项剂量响应研究中，以3-OHB输注率的增加检查了8例HFREF患者。研究3至4：10 HFREF患者和10名年龄匹配的志愿者在交叉设计中随机分配至3小时3-OHB或安慰剂输注。使用11C-乙酸正电子发射断层扫描评估MEE和MVO 2。结果：3-OHB输注将血浆3-OHB的循环水平从0.4 +/- 0.3增加到3.3 +/- 0.4 mm（p <0.001）。 CO升至2.0 +/- 0.2 L/min（P <0.001），因为中风量增加了20 +/- 2 ml（P <0.001），心率为7 +/- 2 BEATS每分钟（BPM） （p <0.001）。左心室射血分数在数值上增加了8 +/- 1％（p <0.001）。在等离子体-3-OHB水平为0.7毫米的情况下，剂量反应的关系显着增加了0.3 l/min（p <0.001）。 3-OHB增加了MVO 2而不会改变MEE。 HFREF专利和年龄匹配的志愿者在MEE和CO方面对3-OHB输注的反应没有差异。结论：3-OHB对HFREF患者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可检测到。在HFREF患者和年龄匹配的志愿者中都观察到3-OHB的血液动力学作用。 3-OHB可能有可能构成HFREF患者的新型治疗原则。
BACKGROUND: 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 doseresponse relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO 2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers. METHODS: 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 doseresponse 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 2 were evaluated using 11C-acetate positron emission tomography. RESULTS: 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 2 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. CONCLUSIONS: 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.