Ketone ester supplementation suppresses cardiac inflammation and improves cardiac energetics in a swine model of acute myocardial infarction

Salva R Yurista; Robert A Eder; Aidan Welsh; William Jiang; Shi Chen; Anna N Foster; Adam Mauskapf; W H Wilson Tang; William J Hucker; Jaume Coll-Font; Anthony Rosenzweig; Christopher T Nguyen

doi:10.1016/j.metabol.2023.155608

Ketone ester supplementation suppresses cardiac inflammation and improves cardiac energetics in a swine model of acute myocardial infarction

Metabolism. 2023 Aug:145:155608. doi: 10.1016/j.metabol.2023.155608. Epub 2023 Jun 1.

Authors

Affiliations

¹ Corrigan Minehan Heart Center, Division of Cardiology, Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA; Cardiovascular Innovation Research Center, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA.
² Corrigan Minehan Heart Center, Division of Cardiology, Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
³ Corrigan Minehan Heart Center, Division of Cardiology, Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Cardiovascular Innovation Research Center, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA.
⁴ Corrigan Minehan Heart Center, Division of Cardiology, Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA.
⁶ Corrigan Minehan Heart Center, Division of Cardiology, Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA; Division of Health Science Technology, Harvard-Massachusetts Institute of Technology, Cambridge, MA, USA; Cardiovascular Innovation Research Center, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: nguyenc6@ccf.org.

PMID: 37268056
PMCID: PMC10330653 (available on 2024-08-01)
DOI: 10.1016/j.metabol.2023.155608

Abstract

Background: Myocardial infarction (MI) is a major risk factor for the development of heart failure with reduce ejection fraction (HFrEF). While previous studies have focused on HFrEF, the cardiovascular effects of ketone bodies in acute MI are unclear. We examined the effects of oral ketone supplementation as a potential treatment strategy in a swine acute MI model.

Methods: Farm pigs underwent percutaneous balloon occlusion of the LAD for 80 min followed by 72 h reperfusion period. Oral ketone ester or vehicle was administered during reperfusion and continued during the follow-up period.

Results: Oral KE supplementation induced ketonemia 2-3 mmol/l within 30 min after ingestion. KE increased ketone (βHB) extraction in healthy hearts without affecting glucose and fatty acid (FA) consumption. During reperfusion, the MI hearts consumed less FA with no change in glucose consumption, whereas hearts from MI-KE-fed animals consumed more βHB and FA, as well as improved myocardial ATP production. A significant elevation of infarct T2 values indicative of inflammation was found only in untreated MI group compared to sham. Concordantly, cardiac expression of inflammatory markers, oxidative stress, and apoptosis were reduced by KE. RNA-seq analysis identified differentially expressed genes related to mitochondrial energy metabolism and inflammation.

Conclusions: Oral KE supplementation induced ketosis and enhanced myocardial βHB extraction in both healthy and infarcted hearts. Acute oral supplementation with KE favorably altered cardiac substrate uptake and utilization, improved cardiac ATP levels, and reduced cardiac inflammation following MI.

Keywords: Inflammation; Ischemia reperfusion injury; Ketone; Ketone ester; Metabolism; Myocardial infarction.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adenosine Triphosphate
Animals
Dietary Supplements
Disease Models, Animal
Glucose / pharmacology
Heart Failure*
Ketones / pharmacology
Myocardial Infarction* / drug therapy
Myocardial Infarction* / metabolism
Stroke Volume
Swine

Substances

Ketones
Adenosine Triphosphate
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding