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

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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 P-3-OHB levels in these patients are unknown. Consequently, our 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: Sixteen chronic HFrEF patients (left ventricular ejection fraction (LVEF) 37±3%) were randomized in a cross-over 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, eight HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3-4: Ten HFrEF patients and 10 age-matched volunteers were randomized in a cross-over design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography.

RESULTS: 1) 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) due to an increase in SV of 20±2ml (p<0.001) and HR of 7±2bpm (p<0.001). LVEF increased 8±1% (p<0.001) numerically. 2) There was a dose-response relationship with a significant CO increase of 0.3 L/min already at P-3-OHB levels of 0.7mM (p <0.001). 3) 3-OHB increased MVO2 without altering MEE. 4) 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.

OriginalsprogEngelsk
TidsskriftCirculation
Vol/bind139
Nummer18
Sider (fra-til)2129-2141
Antal sider13
ISSN0009-7330
DOI
StatusUdgivet - 2019

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