Mitochondrial fatty acid oxidation is the major source of cardiac adenosine triphosphate production in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this stu...

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Published in:Cardiovascular research 2024-03, Vol.120 (4), p.360-371
Main Authors: Sun, Qiuyu, Güven, Berna, Wagg, Cory S, Almeida de Oliveira, Amanda, Silver, Heidi, Zhang, Liyan, Chen, Brandon, Wei, Kaleigh, Ketema, Ezra B, Karwi, Qutuba G, Persad, Kaya L, Vu, Jennie, Wang, Faqi, Dyck, Jason R B, Oudit, Gavin Y, Lopaschuk, Gary D
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
Fatty Acids - metabolism
Glucose - metabolism
Heart Failure
Humans
Insulin - metabolism
Ketones
Male
Mice
Mice, Inbred C57BL
Myocardium - metabolism
Stroke Volume
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Summary:Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this study was to define the energy metabolic profile of the heart in HFpEF. Eight-week-old C57BL/6 male mice were subjected to a '2-Hit' HFpEF protocol [60% high-fat diet (HFD) + 0.5 g/L of Nω-nitro-L-arginine methyl ester]. Echocardiography and pressure-volume loop analysis were used for assessing cardiac function and cardiac haemodynamics, respectively. Isolated working hearts were perfused with radiolabelled energy substrates to directly measure rates of fatty acid oxidation, glucose oxidation, ketone oxidation, and glycolysis. HFpEF mice exhibited increased body weight, glucose intolerance, elevated blood pressure, diastolic dysfunction, and cardiac hypertrophy. In HFpEF hearts, insulin stimulation of glucose oxidation was significantly suppressed. This was paralleled by an increase in fatty acid oxidation rates, while cardiac ketone oxidation and glycolysis rates were comparable with healthy control hearts. The balance between glucose and fatty acid oxidation contributing to overall adenosine triphosphate (ATP) production was disrupted, where HFpEF hearts were more reliant on fatty acid as the major source of fuel for ATP production, compensating for the decrease of ATP originating from glucose oxidation. Additionally, phosphorylated pyruvate dehydrogenase levels decreased in both HFpEF mice and human patient's heart samples. In HFpEF, fatty acid oxidation dominates as the major source of cardiac ATP production at the expense of insulin-stimulated glucose oxidation.
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvae006