bims-hafaim 2025-06-01 papers

Issue of 2025–06–01
five papers selected by
Kyle McCommis, Saint Louis University

ESC Heart Fail. 2025 May 26.

Alterations of myocardial ketone metabolism in heart failure with preserved ejection fraction (HFpEF).

Qiuyu Sun, Cory S Wagg, Nathan Wong, Kaleigh Wei, Ezra B Ketema, Liyan Zhang, Liye Fang, John M Seubert, Gary D Lopaschuk.

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.

DOI: https://doi.org/10.1002/ehf2.15319

Antioxidants (Basel). 2025 May 16. pii: 603. [Epub ahead of print]14(5):

Oral Sulforaphane Intervention Protects Against Diabetic Cardiomyopathy in db/db Mice: Focus on Cardiac Lipotoxicity and Substrate Metabolism.

Pan Wang, Ziling Wang, Xinyuan Jin, Mengdi Zhang, Mengfan Shen, Dan Li.

The protective effect of cruciferae-derived sulforaphane (SFN) on diabetic cardiomyopathy (DCM) has garnered increasing attention. However, no studies have specifically explored its mechanistic involvement in cardiac substrate metabolism and mitochondrial function. To address this gap, Type 2 diabetes mellitus (T2DM) db/db mice were orally gavaged with vehicle or 10 mg/kg body weight SFN every other day for 16 weeks, with vehicle-treated wild-type mice as controls. SFN intervention (SFN-I) alleviated hyperglycemia, dyslipidemia, HOMA-IR, serum MDA levels, and liver inflammation. Furthermore, SFN-I improved the lipotoxicity-related phenotype of T2DM cardiomyopathy, manifested as attenuation of diastolic dysfunction, cardiac injury, fibrosis, lipid accumulation and peroxidation, ROS generation, and decreased mitochondrial complex I and II activities and ATP content, despite having no effect on ceramide abnormalities. Protein expression data revealed that the model mice exhibited upregulated cardiac CD36, H-FABP, FATP4, CPT1B, PPARα, and PDK4 but downregulated GLUT4, with unchanged MPC1 and MPC2. Notably, SFN-I significantly attenuated the increase in CD36, H-FABP, CPT1B, and PPARα. These results suggest that chronic oral SFN-I protects against DCM by mitigating overall metabolic dysregulation and inhibiting cardiolipotoxicity. The latter might involve controlling cardiac fatty acid metabolism and improving mitochondrial function, rather than promoting glucose metabolism.

Keywords: cruciferae; diabetes mellitus; diabetic cardiomyopathy; lipotoxicity; mitochondrial function; substrate metabolism; sulforaphane

DOI: https://doi.org/10.3390/antiox14050603

Am J Physiol Heart Circ Physiol. 2025 May 27.

Relative contribution of correcting the diet and voluntary exercise to myocardial recovery in a murine model of heart failure with preserved ejection fraction.

Emylie-Ann Labbé, Sara-Ève Thibodeau, Èlisabeth Walsh-Wilkinson, Maude Chalifour, Pierre-Olivier Sirois, Juliette Leblanc, Audrey Morin-Grandmont, Marie Arsenault, Jacques Couet.

Using a two-hit murine model of heart failure with preserved ejection fraction (HFpEF), we studied cardiac reverse remodelling (RR) after stopping the causing stress (Angiotensin II (AngII) + High-fat diet (HFD); MHS) and then introducing voluntary exercise (VE) and feeding the animals with a low-fat diet. This led to extensive left ventricle (LV) RR. We then studied the relative contribution to RR of only correcting the diet or allowing VE after stopping AngII. We next evaluated myocardial recovery after an extended period (12 weeks instead of four) by exposing the animals to a second MHS. Our observations revealed a sex-specific response. Stopping AngII but continuing the HFD blocked RR in females, not males. Correcting the diet or implementing VE normalized most gene markers of LV hypertrophy or extracellular matrix remodelling, irrespective of sex. Twelve weeks of recovery was associated with normal LV morphology and function, except for several abnormal diastolic echocardiographic parameters. A second MHS after these 12 weeks led to a loss of ejection fraction in males. The response of females was like that after the first MHS, suggesting a better myocardial recovery. The MHS likely changed myocardial glucose metabolism. Pyruvate dehydrogenase (PDH) activity, which is responsible for pyruvate entry in the mitochondria, was reduced after MHS, and this was accompanied by an increase in PDH phosphorylation and pyruvate dehydrogenase kinase 4 content. RR normalized these. Our results suggest sex-specific RR after stopping the MHS and that myocardial anomalies remaining make males more sensitive to a second HFpEF-inducing stress.

Keywords: HFpEF; cardiac hypertrophy; heart failure; life habits; mouse; myocardial recovery; preclinical model; reverse remodelling

DOI: https://doi.org/10.1152/ajpheart.00092.2025

Int J Mol Sci. 2025 May 19. pii: 4856. [Epub ahead of print]26(10):

Ketone Bodies in the Regulation of Myocardial Perfusion in Cardiovascular Disease: Metabolic and Vasodilatory Effects.

Afolasayo A Aromiwura, Kara R Gouwens, Daniel C Nguyen, Maryta Sztukowska, Luanne Didelot, Dinesh K Kalra.

Ketone bodies (KBs) serve as an alternative energy source for healthy and failing hearts and have important effects on myocardial blood perfusion in both physiological and pathological states. Early animal studies suggest that KBs may provide protective benefits in ischemic heart disease and heart failure. Under normal circumstances, coronary blood flow regulation is an intricate system with contributions from metabolic, autonomic, compressive, and endothelial factors, with the metabolic regulatory pathway being the most significant contributor. We conducted a non-systematic review of studies published between 1987 and 2024. In this review, we explored the physiological autoregulation of normal coronary blood flow, the role of ketone bodies in myocardial perfusion in health and disease, and the potential role of exogenous ketone body supplementation in producing salutary effects on myocardial blood flow (MBF) and metabolism in exercise and cardiac disease states including ischemia, heart failure, and the aging heart. Overall, our findings demonstrated that KBs improve MBF and ejection fraction in healthy human subjects and have beneficial effects on cardiac output and left heart filling pressures in patients with decompensated heart failure. Although resting myocardial blood flow decreases with age, further studies are required to assess the impact of KBs on MBF in aging populations. Additionally, more research is needed to investigate the effects of KBs during exercise and in instances of myocardial ischemia.

Keywords: ketone bodies; metabolic vasodilation; myocardial blood flow

DOI: https://doi.org/10.3390/ijms26104856

Sci Rep. 2025 May 28. 15(1): 18718

Identification of metabolic pathways and serum biomarkers in diabetic cardiomyopathy using untargeted metabolomics.

Jialong Li, Huaming Qiu, Yanjun Wu, Li Su.

Diabetic cardiomyopathy represents a significant and irreversible chronic cardiovascular complication among diabetic patients. The condition is characterised by early diastolic dysfunction, myocardial fibrosis, cardiac hypertrophy, systolic dysfunction, and other complex pathophysiological events that ultimately lead to heart failure. Untargeted metabolomic analysis represents a powerful tool for the discovery of novel biomarkers. It can not only reveal the metabolic disorder model of diabetic cardiomyopathy, and find specific biomarkers, but also help analyse its pathogenesis and provide new clues for developing treatment strategies. Nevertheless, the precise mechanisms that give rise to diabetic cardiomyopathy remain unclear. In this study, we established a rat model of diabetic cardiomyopathy. We evaluated the model using various established methods, including fasting glucose, glycated hemoglobin, insulin resistance index, cardiac histopathology, and cardiac ultrasound. We then proceeded to identify diabetic cardiomyopathy serum biomarkers by untargeted metabolomics. The potential metabolic pathways of the multiple metabolic differentials were mainly related to amino acid metabolism and arachidonic acid metabolism. Two common metabolites, 5-OxoETE and D-Glutamine, were identified through various cross-comparisons. These two metabolites have good diagnostic ability, especially between DCM vs. CTR, DCM vs. NDCM, and NDCM vs. CTR. These findings may provide new insights into the study of DCM.

Keywords: Cardiac ultrasound; Diabetic cardiomyopathy; Diagnostic biomarkers; Ejection fraction; Untargeted metabolomics

DOI: https://doi.org/10.1038/s41598-025-98753-y