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Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients
Aarhus Univ Hosp, Dept Cardiol, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark;Aarhus Univ Hosp, Dept Endocrinol & Metab, Aarhus, Denmark.
Aarhus Univ Hosp, Dept Endocrinol & Metab, Aarhus, Denmark;Aarhus Univ, Dept Clin Med, Fac Hlth, Aarhus, Denmark.ORCID iD: 0000-0001-5627-7322
Aarhus Univ Hosp, Dept Nucl Med, Aarhus, Denmark;Aarhus Univ Hosp, PET Ctr, Aarhus, Denmark;Aarhus Univ, Dept Clin Med, Fac Hlth, Aarhus, Denmark.
Aarhus Univ Hosp, Dept Nucl Med, Aarhus, Denmark;Aarhus Univ Hosp, PET Ctr, Aarhus, Denmark.ORCID iD: 0000-0002-8105-7046
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2019 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 139, no 18, p. 2129-2141Article in journal (Refereed) Published
Abstract [en]

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 doseresponse relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO 2); 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 doseresponse 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 MVO 2 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 MVO 2 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.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS , 2019. Vol. 139, no 18, p. 2129-2141
Keywords [en]
3-hydroxybutyrate, echocardiography, heart failure, ketone bodies, metabolism, positron-emission tomography
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-387208DOI: 10.1161/CIRCULATIONAHA.118.036459ISI: 000468330600008PubMedID: 30884964OAI: oai:DiVA.org:uu-387208DiVA, id: diva2:1330170
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved

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