Alterations of Myocardial Ketone Metabolism in Heart Failure with Preserved Ejection Fraction (HFpEF)
Bibliographic record
Abstract
Abstract Introduction Cardiac energy metabolism is disrupted in heart failure with preserved ejection fraction (HFpEF), as characterized by a switch from glucose oxidation towards fatty acid oxidation. However, although oxidation of ketones is an important source of ATP it remains unclear how the heart oxidizes ketones in HFpEF. It is also unclear whether elevating ketone supply to the heart can improve cardiac energetics and/or provide functional benefit for the hearts in HFpEF. Aims The present study investigated the effects of increasing ketone supply to the heart via ketone supplementation or SGLT2 inhibitor treatment in a mouse model of HFpEF. Methods HFpEF was induced in 13-month-old C57BL/6N female mice with 60% high-fat diet and L-NAME (0.5 g/L/day in the drinking water) for 6 weeks. In parallel, two other groups of mice were maintained on the HFpEF protocol while also receiving either a ketone ester supplement (1–3 butanediol 1 g/kg/day) or SGLT2 inhibitor (empagliflozin 10 mg/kg/day) for 6 weeks. Control mice were fed with regular low-fat diet and regular drinking water. Hearts of the mice were excised and perfused in the isolated working mode aerobically with 5-mM glucose, 0.8-mM palmitate, 100-μU/mL insulin, with either low (0.6 mM) or high (1 mM) levels of β-hydroxybutyrate. Metabolic rates of the hearts were measured with radiolabelled [U-14C] glucose, [9,10-3H] palmitate and [3-14C] β-hydroxybutyrate. Results In HFpEF mouse hearts, glucose oxidation was significantly decreased with a parallel increase in fatty acid oxidation. Increasing β-hydroxybutyrate levels from 0.6 to 1 mM in the perfusate resulted in a rise in ketone oxidation rates in control hearts (from 861 ± 63 to 1377 ± 94 nmol g dry wt−1 min−1), which was muted in HFpEF hearts (from 737 ± 68 to 897 ± 134 nmol g dry wt−1 min−1). Following ketone ester supplement or SGLT2 inhibitor treatment, HFpEF mice presented with restored ketone oxidation rates (from 674 ± 36 to 1181 ± 115 nmol g dry wt−1 min−1 with ketone ester supplement and from 797 ± 121 to 1240 ± 120 nmol g dry wt−1 min−1 with SGLT2i). Yet, this was not associated with improvement in cardiac function. Conclusions In HFpEF mice, the heart switches from glucose oxidation to fatty acid oxidation, with ketone oxidation being impaired. Increasing ketone supply to the heart via ketone ester supplementation or SGLT2 inhibitor treatment increases myocardial ketone oxidation rates but was not associated with functional improvements. Unlike HFrEF, ketone supplementation strategies may be less effective in HFpEF due to an impairment of myocardial ketone oxidation in HFpEF.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".