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.