Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation
Abstract Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia–reperfusion injury, presumably by impro...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-51387-y |
| _version_ | 1827382179597910016 |
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| author | Jacob Marthinsen Seefeldt Yaara Libai Katrine Berg Nichlas Riise Jespersen Thomas Ravn Lassen Frederik Flyvholm Dalsgaard Pia Ryhammer Michael Pedersen Lars Bo Ilkjaer Michiel A. Hu Michiel E. Erasmus Roni R. Nielsen Hans Erik Bøtker Oren Caspi Hans Eiskjær Niels Moeslund |
| author_facet | Jacob Marthinsen Seefeldt Yaara Libai Katrine Berg Nichlas Riise Jespersen Thomas Ravn Lassen Frederik Flyvholm Dalsgaard Pia Ryhammer Michael Pedersen Lars Bo Ilkjaer Michiel A. Hu Michiel E. Erasmus Roni R. Nielsen Hans Erik Bøtker Oren Caspi Hans Eiskjær Niels Moeslund |
| author_sort | Jacob Marthinsen Seefeldt |
| collection | DOAJ |
| description | Abstract Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia–reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer’s acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function. |
| first_indexed | 2024-03-08T14:15:49Z |
| format | Article |
| id | doaj.art-1a66841ddc5640f09a88e154cc730f6c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-08T14:15:49Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1a66841ddc5640f09a88e154cc730f6c2024-01-14T12:21:45ZengNature PortfolioScientific Reports2045-23222024-01-0114111210.1038/s41598-024-51387-yEffects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantationJacob Marthinsen Seefeldt0Yaara Libai1Katrine Berg2Nichlas Riise Jespersen3Thomas Ravn Lassen4Frederik Flyvholm Dalsgaard5Pia Ryhammer6Michael Pedersen7Lars Bo Ilkjaer8Michiel A. Hu9Michiel E. Erasmus10Roni R. Nielsen11Hans Erik Bøtker12Oren Caspi13Hans Eiskjær14Niels Moeslund15Department of Cardiology, Aarhus University HospitalThe Laboratory for Cardiovascular Precision Medicine, Rapport Faculty of Medicine, Technion and Rambam’s Cardiovascular Research and Innovation CenterDepartment of Cardiology, Aarhus University HospitalDepartment of Cardiology, Aarhus University HospitalDepartment of Cardiology, Aarhus University HospitalDepartment of Cardiology, Aarhus University HospitalDepartment of Anesthesiology, Regional Hospital SilkeborgComparative Medicine Lab, Department of Clinical Medicine, Aarhus UniversityDepartment of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Palle Juul-JensensDepartment of Cardiothoracic Surgery, University Medical Center GroningenDepartment of Cardiothoracic Surgery, University Medical Center GroningenDepartment of Cardiology, Aarhus University HospitalDepartment of Clinical Medicine, Aarhus UniversityThe Laboratory for Cardiovascular Precision Medicine, Rapport Faculty of Medicine, Technion and Rambam’s Cardiovascular Research and Innovation CenterDepartment of Cardiology, Aarhus University HospitalDepartment of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Palle Juul-JensensAbstract Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia–reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer’s acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function.https://doi.org/10.1038/s41598-024-51387-y |
| spellingShingle | Jacob Marthinsen Seefeldt Yaara Libai Katrine Berg Nichlas Riise Jespersen Thomas Ravn Lassen Frederik Flyvholm Dalsgaard Pia Ryhammer Michael Pedersen Lars Bo Ilkjaer Michiel A. Hu Michiel E. Erasmus Roni R. Nielsen Hans Erik Bøtker Oren Caspi Hans Eiskjær Niels Moeslund Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation Scientific Reports |
| title | Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation |
| title_full | Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation |
| title_fullStr | Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation |
| title_full_unstemmed | Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation |
| title_short | Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation |
| title_sort | effects of ketone body 3 hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation |
| url | https://doi.org/10.1038/s41598-024-51387-y |
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