Enantiomer‐Specific Cardiovascular Effects of the Ketone Body 3‐Hydroxybutyrate

• DOI: 10.1161/jaha.123.033628
• Publication Date: 2024-04-02T13:45:03Z
• Authors: Nigopan Gopalasingam; Niels Moeslund; Kristian Hylleber...; Kristoffer Berg‐H...; Jacob Seefeldt; Casper Homilius; Erik Nguyen Nielsen; Mie Ringgaard Dol...; Aage K. Alstrup O...; Mogens Johannsen; Ebbe Boedtkjer; Niels Møller; Hans Eiskjær; Lars Christian Go...; Roni Nielsen; Henrik Wiggers
• Keywords: Cross-Over Studies; Swine; 3-Hydroxybutyric Acid/pharmacology; ketone; heart failure; Heart; hemodynamics; 3‐hydroxybutyrate; RC666-701; Ketone Bodies/metabolism; Humans; Animals; Diseases of the circulatory (Cardiovascular) system; pressure‐volume loop; Tomography, X-Ray Computed; pharmacokinetics; metabolism; Hydroxybutyrates/pharmacology; Original Research

Background The 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 Results

Three 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‐[ 11 C]3‐OHB and L‐[ 11 C]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‐[ 11 C]3‐OHB showed rapid cardiac uptake and metabolism, whereas L‐[ 11 C]3‐OHB demonstrated much slower pharmacokinetics.

Conclusions 3‐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.