Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate

Nigopan Gopalasingam; Niels Moeslund; Kristian Hylleberg Christensen; Kristoffer Berg-Hansen; Jacob Seefeldt; Casper Homilius; Erik Nguyen Nielsen; Mie Ringgaard Dollerup; Aage K Alstrup Olsen; Mogens Johannsen; Ebbe Boedtkjer; Niels Møller; Hans Eiskjær; Lars Christian Gormsen; Roni Nielsen; Henrik Wiggers

doi:10.1161/JAHA.123.033628

Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate

Nigopan Gopalasingam, Niels Moeslund, Kristian Hylleberg Christensen, Kristoffer Berg-Hansen, Jacob Seefeldt, Casper Homilius, Erik Nguyen Nielsen, Mie Ringgaard Dollerup, Aage K Alstrup Olsen, Mogens Johannsen, Ebbe Boedtkjer, Niels Møller, Hans Eiskjær, Lars Christian Gormsen, Roni Nielsen, Henrik Wiggers

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Abstract

BACKGROUND: The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3-OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D-3-OHB and L-3-OHB, remain undetermined. METHODS AND RESULTS: Three groups of 8 pigs each underwent a randomized, crossover study. The groups received 3-hour infusions of either D/L-3-OHB (racemic mixture), 100% L-3-OHB, 100% D-3-OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure-volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high-resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D-[¹¹C]3-OHB and L-[¹¹C]3-OHB positron emission tomography. All three 3-OHB infusions increased 3-OHB levels (P<0.001). D/L-3-OHB and L-3-OHB increased CO by 2.7 L/min (P<0.003). D-3-OHB increased CO nonsignificantly (P=0.2). Circulating 3-OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, Dand L-3-OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3-OHB extraction increased only during the D-and D/L-3-OHB infusions. D-[¹¹C]3-OHB showed rapid cardiac uptake and metabolism, whereas L-[¹¹C]3-OHB demonstrated much slower pharmacokinetics. CONCLUSIONS: 3-OHB increased CO by reducing afterload. L-3-OHB exerted a stronger hemodynamic response than D-3OHB due to higher circulating 3-OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L-3-OHB as a potent cardiovascular agent with strong hemodynamic effects.

Originalsprog	Engelsk
Artikelnummer	e033628
Tidsskrift	Journal of the American Heart Association
Vol/bind	13
Nummer	8
Sider (fra-til)	e033628
Antal sider	18
ISSN	2047-9980
DOI	https://doi.org/10.1161/JAHA.123.033628
Status	Udgivet - apr. 2024

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10.1161/JAHA.123.033628Licens: CC BY-NC-ND

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Gopalasingam, N., Moeslund, N., Christensen, K. H., Berg-Hansen, K., Seefeldt, J., Homilius, C., Nielsen, E. N., Dollerup, M. R., Alstrup Olsen, A. K., Johannsen, M., Boedtkjer, E., Møller, N., Eiskjær, H., Gormsen, L. C., Nielsen, R., & Wiggers, H. (2024). Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate. Journal of the American Heart Association, 13(8), e033628. Artikel e033628. https://doi.org/10.1161/JAHA.123.033628

@article{b5468f33d70d4e6baa2c2253001e1203,

title = "Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate",

abstract = "BACKGROUND: The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3-OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D-3-OHB and L-3-OHB, remain undetermined. METHODS AND RESULTS: Three groups of 8 pigs each underwent a randomized, crossover study. The groups received 3-hour infusions of either D/L-3-OHB (racemic mixture), 100% L-3-OHB, 100% D-3-OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure-volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high-resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D-[11C]3-OHB and L-[11C]3-OHB positron emission tomography. All three 3-OHB infusions increased 3-OHB levels (P<0.001). D/L-3-OHB and L-3-OHB increased CO by 2.7 L/min (P<0.003). D-3-OHB increased CO nonsignificantly (P=0.2). Circulating 3-OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, Dand L-3-OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3-OHB extraction increased only during the D-and D/L-3-OHB infusions. D-[11C]3-OHB showed rapid cardiac uptake and metabolism, whereas L-[11C]3-OHB demonstrated much slower pharmacokinetics. CONCLUSIONS: 3-OHB increased CO by reducing afterload. L-3-OHB exerted a stronger hemodynamic response than D-3OHB due to higher circulating 3-OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L-3-OHB as a potent cardiovascular agent with strong hemodynamic effects.",

keywords = "Humans, Swine, Animals, 3-Hydroxybutyric Acid/pharmacology, Cross-Over Studies, Tomography, X-Ray Computed, Hydroxybutyrates/pharmacology, Heart, Ketone Bodies/metabolism, heart failure, pressure‐volume loop, hemodynamics, ketone, 3‐hydroxybutyrate, pharmacokinetics, metabolism",

author = "Nigopan Gopalasingam and Niels Moeslund and Christensen, {Kristian Hylleberg} and Kristoffer Berg-Hansen and Jacob Seefeldt and Casper Homilius and Nielsen, {Erik Nguyen} and Dollerup, {Mie Ringgaard} and {Alstrup Olsen}, {Aage K} and Mogens Johannsen and Ebbe Boedtkjer and Niels M{\o}ller and Hans Eiskj{\ae}r and Gormsen, {Lars Christian} and Roni Nielsen and Henrik Wiggers",

year = "2024",

month = apr,

doi = "10.1161/JAHA.123.033628",

language = "English",

volume = "13",

pages = "e033628",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

publisher = "Wiley-Blackwell Publishing, Inc.",

number = "8",

}

Gopalasingam, N , Moeslund, N , Christensen, KH , Berg-Hansen, K , Seefeldt, J , Homilius, C , Nielsen, EN, Dollerup, MR, Alstrup Olsen, AK , Johannsen, M , Boedtkjer, E , Møller, N, Eiskjær, H, Gormsen, LC , Nielsen, R & Wiggers, H 2024, 'Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate', Journal of the American Heart Association, bind 13, nr. 8, e033628, s. e033628. https://doi.org/10.1161/JAHA.123.033628

Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate. / Gopalasingam, Nigopan ; Moeslund, Niels ; Christensen, Kristian Hylleberg et al.
I: Journal of the American Heart Association, Bind 13, Nr. 8, e033628, 04.2024, s. e033628.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate

AU - Gopalasingam, Nigopan

AU - Moeslund, Niels

AU - Christensen, Kristian Hylleberg

AU - Berg-Hansen, Kristoffer

AU - Seefeldt, Jacob

AU - Homilius, Casper

AU - Nielsen, Erik Nguyen

AU - Dollerup, Mie Ringgaard

AU - Alstrup Olsen, Aage K

AU - Johannsen, Mogens

AU - Boedtkjer, Ebbe

AU - Møller, Niels

AU - Eiskjær, Hans

AU - Gormsen, Lars Christian

AU - Nielsen, Roni

AU - Wiggers, Henrik

PY - 2024/4

Y1 - 2024/4

N2 - BACKGROUND: The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3-OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D-3-OHB and L-3-OHB, remain undetermined. METHODS AND RESULTS: Three groups of 8 pigs each underwent a randomized, crossover study. The groups received 3-hour infusions of either D/L-3-OHB (racemic mixture), 100% L-3-OHB, 100% D-3-OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure-volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high-resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D-[11C]3-OHB and L-[11C]3-OHB positron emission tomography. All three 3-OHB infusions increased 3-OHB levels (P<0.001). D/L-3-OHB and L-3-OHB increased CO by 2.7 L/min (P<0.003). D-3-OHB increased CO nonsignificantly (P=0.2). Circulating 3-OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, Dand L-3-OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3-OHB extraction increased only during the D-and D/L-3-OHB infusions. D-[11C]3-OHB showed rapid cardiac uptake and metabolism, whereas L-[11C]3-OHB demonstrated much slower pharmacokinetics. CONCLUSIONS: 3-OHB increased CO by reducing afterload. L-3-OHB exerted a stronger hemodynamic response than D-3OHB due to higher circulating 3-OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L-3-OHB as a potent cardiovascular agent with strong hemodynamic effects.

AB - BACKGROUND: The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3-OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D-3-OHB and L-3-OHB, remain undetermined. METHODS AND RESULTS: Three groups of 8 pigs each underwent a randomized, crossover study. The groups received 3-hour infusions of either D/L-3-OHB (racemic mixture), 100% L-3-OHB, 100% D-3-OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure-volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high-resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D-[11C]3-OHB and L-[11C]3-OHB positron emission tomography. All three 3-OHB infusions increased 3-OHB levels (P<0.001). D/L-3-OHB and L-3-OHB increased CO by 2.7 L/min (P<0.003). D-3-OHB increased CO nonsignificantly (P=0.2). Circulating 3-OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, Dand L-3-OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3-OHB extraction increased only during the D-and D/L-3-OHB infusions. D-[11C]3-OHB showed rapid cardiac uptake and metabolism, whereas L-[11C]3-OHB demonstrated much slower pharmacokinetics. CONCLUSIONS: 3-OHB increased CO by reducing afterload. L-3-OHB exerted a stronger hemodynamic response than D-3OHB due to higher circulating 3-OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L-3-OHB as a potent cardiovascular agent with strong hemodynamic effects.

KW - Humans

KW - Swine

KW - Animals

KW - 3-Hydroxybutyric Acid/pharmacology

KW - Cross-Over Studies

KW - Tomography, X-Ray Computed

KW - Hydroxybutyrates/pharmacology

KW - Heart

KW - Ketone Bodies/metabolism

KW - heart failure

KW - pressure‐volume loop

KW - hemodynamics

KW - ketone

KW - 3‐hydroxybutyrate

KW - pharmacokinetics

KW - metabolism

UR - http://www.scopus.com/inward/record.url?scp=85190900736&partnerID=8YFLogxK

U2 - 10.1161/JAHA.123.033628

DO - 10.1161/JAHA.123.033628

M3 - Journal article

C2 - 38563382

SN - 2047-9980

VL - 13

SP - e033628

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 8

M1 - e033628

ER -

Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate

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