BackgroundThe ketone body 3‐hydroxybutyrate (3‐OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3‐OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D‐3‐OHB and L‐3‐OHB, remain undetermined.Methods and ResultsThree groups of 8 pigs each underwent a randomized, crossover study. The groups received 3‐hour infusions of either D/L‐3‐OHB (racemic mixture), 100% L‐3‐OHB, 100% D‐3‐OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure‐volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high‐resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D‐[¹¹C]3‐OHB and L‐[¹¹C]3‐OHB positron emission tomography. All three 3‐OHB infusions increased 3‐OHB levels (P<0.001). D/L‐3‐OHB and L‐3‐OHB increased CO by 2.7 L/min (P<0.003). D‐3‐OHB increased CO nonsignificantly (P=0.2). Circulating 3‐OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, D‐ and L‐3‐OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3‐OHB extraction increased only during the D‐ and D/L‐3‐OHB infusions. D‐[¹¹C]3‐OHB showed rapid cardiac uptake and metabolism, whereas L‐[¹¹C]3‐OHB demonstrated much slower pharmacokinetics.Conclusions3‐OHB increased CO by reducing afterload. L‐3‐OHB exerted a stronger hemodynamic response than D‐3‐OHB due to higher circulating 3‐OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L‐3‐OHB as a potent cardiovascular agent with strong hemodynamic effects.

中文翻译：

---

酮体 3-羟基丁酸酯对映体特异性心血管作用

背景酮体 3-羟基丁酸酯 (3-OHB) 可使健康人和心力衰竭患者的心输出量 (CO) 增加 35% 至 40%。 3-OHB 对心肌收缩力和负荷条件的影响及其对映体形式 D-3-OHB 和 L-3-OHB 的心血管影响的机制尚未确定。 方法和结果 三组，每组 8 头猪，进行了试验一项随机交叉研究。与等容对照相比，各组接受 3 小时的 D/L-3-OHB（外消旋混合物）、100% L-3-OHB、100% D-3-OHB 输注。使用肺动脉导管、左心室压力容量导管以及动脉和冠状窦血样对动物进行监测。使用高分辨率呼​​吸测量法评估心肌活检，使用等长肌造影评估冠状动脉，并使用 D-[ ¹¹ C]3-OHB 和 L-[ ¹¹ C]3-OHB 正电子发射断层扫描评估心肌动力学。所有三种 3-OHB 输注均增加了 3-OHB 水平（P <0.001）。 D/L-3-OHB 和 L-3-OHB 使 CO 增加 2.7 L/min ( P <0.003)。 D-3-OHB 不显着地增加 CO（P = 0.2）。两种对映体的循环 3-OHB 水平与 CO 相关（P <0.001）。 CO 增加是通过动脉弹性（后负荷）减少介导的，而收缩性和前负荷则没有变化。离体时，D-和 L-3-OHB 同等程度地扩张冠状动脉。线粒体呼吸能力不受影响。心肌 3-OHB 提取仅在 D- 和 D/L-3-OHB 输注期间增加。 D-[ ¹¹ C]3-OHB 表现出快速的心脏摄取和代谢，而 L-[ ¹¹ C]3-OHB 表现出慢得多的药代动力学。结论 3-OHB 通过减少后负荷来增加 CO。由于循环 3-OHB 水平较高，L-3-OHB 比 D-3-OHB 产生更强的血流动力学反应。对映体的心肌代谢和血流动力学效应之间存在分离，凸显了 L-3-OHB 作为一种有效的心血管药物，具有很强的血流动力学效应。