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

Area of Science:

• Cardiovascular Physiology
• Metabolic Biochemistry

Background:

• Ketone body 3-hydroxybutyrate (3-OHB) is known to increase cardiac output (CO) in healthy individuals and those with heart failure.
• The precise mechanisms behind 3-OHB's effects on myocardial contractility, loading conditions, and the distinct cardiovascular impacts of its enantiomers (D-3-OHB and L-3-OHB) are not fully understood.

Purpose of the Study:

• To investigate the hemodynamic effects of D-3-OHB, L-3-OHB, and a racemic mixture (D/L-3-OHB) on cardiac output.
• To elucidate the mechanisms by which 3-OHB influences cardiovascular function, including its impact on afterload, contractility, and preload.
• To compare the cardiovascular effects and myocardial kinetics of the D- and L-enantiomers of 3-OHB.

Main Methods:

• A randomized, crossover study was conducted in pigs, with infusions of D/L-3-OHB, L-3-OHB, D-3-OHB, and an isovolumic control.
• Hemodynamic parameters were monitored using pulmonary artery and left ventricle pressure-volume catheters.
• Myocardial biopsies were analyzed for respiratory capacity, coronary arteries for vasodilation, and myocardial kinetics were assessed using positron emission tomography with radiolabeled enantiomers.

Main Results:

• All 3-OHB infusions significantly increased circulating 3-OHB levels.
• Both D/L-3-OHB and L-3-OHB infusions led to a significant increase in cardiac output, primarily mediated by a reduction in arterial elastance (afterload).
• L-3-OHB demonstrated a more potent hemodynamic response compared to D-3-OHB, despite similar coronary artery dilation; myocardial metabolism and mitochondrial respiration remained largely unaffected.

Conclusions:

• 3-Hydroxybutyrate increases cardiac output by decreasing systemic afterload.
• The L-enantiomer of 3-OHB elicits a stronger hemodynamic response than the D-enantiomer, attributed to higher circulating levels.
• A dissociation exists between the myocardial metabolism and hemodynamic effects of 3-OHB enantiomers, positioning L-3-OHB as a promising cardiovascular agent.