Hemodynamic Effects of Ketone Bodies in Patients With Pulmonary Hypertension

Abstract

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.

Keywords: echocardiography; invasive hemodynamics; ketone bodies; pulmonary arterial hypertension.

Figure 1. Changes in plasma 3‐OHB levels, cardiac output, pulmonary vascular resistance, and SVO₂ during the study.

A, 3‐OHB levels were low until 3‐OHB infusion was initiated and decreased after 3‐OHB was substituted with placebo. B, Cardiac output increased from placebo to 3‐OHB infusion and decreased when 3‐OHB infusion was terminated. Pulmonary vascular resistance decreased (C) whereas SVO₂ increased (D) during 3‐OHB infusion. Mean with bars indicating SEM. Crossover was performed following the measurements at 120 minutes (ie, 120–150 minutes). 3‐OHB indicates 3‐hydroxybutyrate; PVR, pulmonary vascular resistance; and SVO₂, mixed venous saturation.

Figure 2. Mean relative hemodynamic change with SEM and the corresponding mean absolute change±SEM listed above or below each bar.

^†Denotes relative changes with a P value <0.05. 3‐OHB indicates 3‐hydroxybutyrate; CO, cardiac output; HR, heart rate; LV‐GLS, left ventricular global longitudinal strain; MAP, mean arterial pressure; mPAP, mean pulmonary pressure; PVR, pulmonary vascular resistance; RV‐GLS, right ventricular global longitudinal strain; RV‐S′, right ventricular systolic tricuspid annular velocity; SV, stroke volume; SVO₂, mixed venous saturation measured in the pulmonary artery; SVR, systemic vascular resistance; TAPSE, tricuspid annular plane systolic excursion; and WU, Wood units.

Figure 3. Right ventricular (RV) pressure (A) and dP/dtmax in the isolated rat heart (B) during increased diastolic pressure at 10 mmol/L NaCl (red line) vs 10 mmol/L Na‐3‐OHB (black line).

No difference was observed in RV systolic pressure (P=0.63), but RV dP/dtmax (P=0.02) was lower in the group receiving 3‐OHB. Mean with bars indicating standard error of mean. 3‐OHB indicates sodium‐3‐hydroxybutyrate; NaCl, sodium chloride; and RV, right ventricle.

Figure 4. Relative changes in pulmonary arterial tension (isolated rat pulmonary arteries).

Tension increased in response to both solutions but was lower with Na‐3‐OHB (P<0.001). Mean with bars indicating SEM. 3‐OHB indicates sodium‐3‐hydroxybutyrate; and NaCl, sodium chloride.