Stimulation of the Hydroxycarboxylic Acid Receptor 2 With the Ketone Body 3‐Hydroxybutyrate and Niacin in Patients With Chronic Heart Failure: Hemodynamic and Metabolic Effects

BACKGROUND: The ketone body 3‐hydroxybutyrate (3‐OHB) increases cardiac output (CO) in patients with heart failure through unknown mechanisms. 3‐OHB activates the hydroxycarboxylic acid receptor 2 (HCA(2)), which increases prostaglandins and suppresses circulating free fatty acids. We investigated whether the cardiovascular effects of 3‐OHB involved HCA(2) activation and if the potent HCA(2)‐stimulator niacin may increase CO. METHODS AND RESULTS: Twelve patients with heart failure with reduced ejection fraction were included in a randomized crossover study and examined by right heart catheterization, echocardiography, and blood sampling on 2 separate days. On study day 1, patients received aspirin to block the HCA(2) downstream cyclooxygenase enzyme, followed by 3‐OHB and placebo infusions in random order. We compared the results with those of a previous study in which patients received no aspirin. On study day 2, patients received niacin and placebo. The primary end point was CO. 3‐OHB increased CO (2.3 L/min, P<0.01), stroke volume (19 mL, P<0.01), heart rate (10 bpm, P<0.01), and mixed venous saturation (5%, P<0.01) with preceding aspirin. 3‐OHB did not change prostaglandin levels, neither in the ketone/placebo group receiving aspirin nor the previous study cohort. Aspirin did not block 3‐OHB‐induced changes in CO (P=0.43). 3‐OHB decreased free fatty acids by 58% (P=0.01). Niacin increased prostaglandin D(2) levels by 330% (P<0.02) and reduced free fatty acids by 75% (P<0.01) but did not affect CO. CONCLUSIONS: The acute increase in CO during 3‐OHB infusion was not modified by aspirin, and niacin had no hemodynamic effects. These findings show that HCA(2) receptor‐mediated effects were not involved in the hemodynamic response to 3‐OHB. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04703361.