Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients

Roni Nielsen, Niels Møller, Lars C Gormsen, Lars Poulsen Tolbod, Nils Henrik Hansson, Jens Sorensen, Hendrik Johannes Harms, Jørgen Frøkiær, Hans Eiskjaer, Nichlas Riise Jespersen, Søren Mellemkjaer, Thomas Ravn Lassen, Kasper Pryds, Hans Erik Bøtker, Henrik Wiggers, Roni Nielsen, Niels Møller, Lars C Gormsen, Lars Poulsen Tolbod, Nils Henrik Hansson, Jens Sorensen, Hendrik Johannes Harms, Jørgen Frøkiær, Hans Eiskjaer, Nichlas Riise Jespersen, Søren Mellemkjaer, Thomas Ravn Lassen, Kasper Pryds, Hans Erik Bøtker, Henrik Wiggers

Abstract

Background: Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors' aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers.

Methods: Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography.

Results: 3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM ( P<0.001). CO rose by 2.0±0.2 L/min ( P<0.001) because of an increase in stroke volume of 20±2 mL ( P<0.001) and heart rate of 7±2 beats per minute (bpm) ( P<0.001). Left ventricular ejection fraction increased 8±1% ( P<0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM ( P<0.001). 3-OHB increased MVO2 without altering MEE. The response to 3-OHB infusion in terms of MEE and CO did not differ between HFrEF patents and age-matched volunteers.

Conclusions: 3-OHB has beneficial hemodynamic effects in HFrEF patients without impairing MEE. These beneficial effects are detectable in the physiological concentration range of circulating 3-OHB levels. The hemodynamic effects of 3-OHB were observed in both HFrEF patients and age-matched volunteers. 3-OHB may potentially constitute a novel treatment principle in HFrEF patients.

Keywords: 3-hydroxybutyrate; echocardiography; heart failure; ketone bodies; metabolism; positron-emission tomography.

Figures

Figure 1.
Figure 1.
Study flowchart. The figure depicts the flow in each study. End point measurements lasted approximately 15 (Studies 1 and 2) to 30 (Studies 3 and 4) minutes. During measurements, the infusions were continued. The subsequent study arm was postponed accordingly to ensure either 3 (Studies 1, 3, and 4) or 2 hours (Study 2) for each infusion. In Study 4, placebo infusion was followed by 25% (1/4) of the 3-OHB dosage in Study 1 and then increased to 50% (1/2). Blood was sampled, and invasive hemodynamic measures were recorded repeatedly throughout the studies. 3-OHB indicates 3-betahydroxybutyrate; echo, echocardiography; IV, intravenous; meas, measurements; and PET, positron emission tomography.
Figure 2.
Figure 2.
Circulating P-3-OHB levels (Study 1) and changes in cardiac output in HFrEF patients (Studies 1 and 2). Mean with bars indicating standard deviation (A and B) or SEM (C). A, P-3-OHB levels were low until 3-OHB infusion was initiated and decreased after 3-OHB was substituted with placebo (n=16). B, Cardiac output increased from placebo to 3-OHB infusion and decreased when 3-OHB infusion was terminated (n=16). C, CO was assessed in Study 2 (n=8) at a low infusion rate (0.045 g · kg-1 · h-1, mean P-3-OHB: 0.7 mM) and an intermediate infusion rate (0.09 g · kg-1 · h-1, mean P-3-OHB: 1.6 mM; paired analysis). These results were compared with those obtained in Study 1 (high infusion rate [0.18 g · kg-1 · h-1], mean P-3-OHB: 3.3 mM, n=16; unpaired data) and demonstrated a dose-response association. 3-OHB indicates 3-betahydroxybutyrate; and CO, cardiac output.
Figure 3.
Figure 3.
Changes in myocardial external efficiency in Studies 3 and 4. MEE was significantly lower in HFrEF patients (n=8) than in age-matched subjects (n=8) (P<0.001), but 3-OHB did not affect MEE in either study group. 3-OHB indicates 3-betahydroxybutyrate; and MEE, myocardial external efficiency.
Figure 4.
Figure 4.
Changes in end point parameters from placebo to 3-OHB infusion. Mean relative change with SEM and the corresponding mean absolute change±SEM listed above or below each bar, respectively. Bpm indicates beats per minute; CO, cardiac output; HR, heart rate; LVEF, left ventricular ejection fraction (Study 1, n=16); MAP, mean arterial pressure; MEE, myocardial external efficiency (Studies 3 and 4, n=20); mPAP, mean pulmonary pressure; PVR, pulmonary vascular resistance; SV, stroke volume; SVO2, mixed venous saturation measured in the pulmonary artery; and SVR, systemic vascular resistance.

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