Søren Mellemkjær

Background Pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) are debilitating diseases with a high mortality. Despite emerging treatments, pulmonary vascular resistance frequently remains elevated. However, the ketone body 3‐hydroxybutyrate (3‐OHB) may reduce pulmonary vascular resistance in these patients. Hence, the aim was to assess the hemodynamic effects of 3‐OHB in patients with PAH or CTEPH. Methods and Results We enrolled patients with PAH (n=10) or CTEPH (n=10) and residual pulmonary hypertension. They received 3‐OHB infusion and placebo (saline) for 2 hours in a randomized crossover study. Invasive hemodynamic and echocardiography measurements were performed. Furthermore, we investigated the effects of 3‐OHB on the right ventricle of isolated hearts and isolated pulmonary arteries from Sprague–Dawley rats. Ketone body infusion increased circulating 3‐OHB levels from 0.5±0.5 to 3.4±0.7 mmol/L ( P <0.001). Cardiac output improved by 1.2±0.1 L/min (27±3%, P <0.001), and right ventricular annular systolic velocity increased by 1.4±0.4 cm/s (13±4%, P =0.002). Pulmonary vascular resistance decreased by 1.3±0.3 Wood units (18%±4%, P <0.001) with no significant difference in response between patients with PAH and CTEPH. In the rat studies, 3‐OHB administration was associated with decreased pulmonary arterial tension compared with saline administration (maximal relative tension difference: 12±2%, P <0.001) and had no effect on right ventricular systolic pressures ( P =0.63), whereas pressures rose at a slower pace (dP/dtmax, P =0.02). Conclusions In patients with PAH or CTEPH, ketone body infusion improves cardiac output and decreases pulmonary vascular resistance. Experimental rat studies support that ketone bodies relax pulmonary arteries. Long‐term studies are warranted to assess the clinical role of hyperketonemia. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04615754.