bims-hafaim 2025-03-16 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–03–16
six papers selected by
Kyle McCommis, Saint Louis University

Cardiac energy metabolic disorder and gut microbiota imbalance: a study on the therapeutic potential of Shenfu Injection in rats with heart failure.
Myocardial ketone body oxidation contributes to empagliflozin-induced improvements in cardiac contractility in murine heart failure.
Sex-Specific Improvements in Myocardial Function and Angiogenesis with SGLT-2 Inhibitor Canagliflozin in a Swine Model of Metabolic Syndrome.
Beyond the gut: Systemic levels of short-chain fatty acids are altered in patients with heart failure.
Association of plasma metabolites and cardiac mitochondrial function with heart failure progression.
Myocardial Proteome in Human Heart Failure With Preserved Ejection Fraction.

Front Microbiol. 2025 ;16 1509548

Cardiac energy metabolic disorder and gut microbiota imbalance: a study on the therapeutic potential of Shenfu Injection in rats with heart failure.

Zhenyu Zhao, Zhixi Hu, Lin Li.

   Objective: To investigate the relationship between heart failure (HF) and gut microbiota-mediated energy metabolism, and to explore the role of Shenfu Injection in this process.
Materials and methods: In this study, Adriamycin-induced chronic heart failure (CHF) rat model was used and randomly divided into the blank control group (Normal, n = 9), HF control group (Model, n = 12), Shenfu Injection treatment group (SFI, n = 9), and positive drug control group (TMZ, n = 9). The changes in gut microbiota structure were analyzed by 16S rRNA high-throughput sequencing, the content of short-chain fatty acids (SCFAs) was detected by targeted metabolomics technology, and cardiac function and energy metabolism-related indicators were evaluated.
Results: Myocardial energy metabolism in HF rats was disordered, characterized by reduced fatty acid oxidation, enhanced anaerobic glycolysis of glucose, mitochondrial damage, and decreased ATP content; The gut microbiota of HF rats was imbalanced, with a reduction in beneficial bacteria, an increase in conditional pathogenic bacteria, and impaired intestinal barrier function; Both Shenfu Injection and trimetazidine improved myocardial energy metabolism and cardiac function, but Shenfu Injection was more significant in regulating gut microbiota and improving intestinal health; The production of SCFAs from the gut microbiota of HF rats increased, which may be closely related to myocardial energy metabolism; SCFAs-producing bacteria Akkermansia and Blautia played a key role in the development of HF, and their abundance was positively correlated with SCFAs content.
Conclusion: Shenfu Injection in treating HF may improve myocardial energy metabolism and intestinal health by regulating gut microbiota, especially the abundance of SCFAs-producing bacteria Akkermansia and Blautia, thereby exerting therapeutic effects. This provides theoretical support for treatment strategies based on gut microbiota.

Keywords:  Shenfu Injection; gut microbiota; heart failure; intestinal barrier function; myocardial energy metabolism; short-chain fatty acids

DOI:  https://doi.org/10.3389/fmicb.2025.1509548
Eur J Heart Fail. 2025 Mar 11.

Myocardial ketone body oxidation contributes to empagliflozin-induced improvements in cardiac contractility in murine heart failure.

Suzanne Nathalie Voorrips, Constantin Laurent Palm, Huitzilihuitl Saucedo-Orozco, Belend Mahmoud, Elisabeth Marloes Schouten, Anna M Feringa, Pablo I Sanchez-Aguilera, Kirsten T Nijholt, Salva R Yurista, Peter van der Meer, Herman H W Silljé, B Daan Westenbrink.

   AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve cardiac performance and clinical outcomes in patients with heart failure, yet mechanisms underlying these beneficial effects remain incompletely understood. We sought to determine whether SGLT2i-induced improvements in cardiac function are dependent on increased cardiac oxidation of ketone bodies.
METHODS AND RESULTS: We employed a mouse model with a cardiac-specific knock-out of the enzyme D-β-hydroxybutyrate dehydrogenase-1 (BDH1cko), rendering mice incapable of oxidizing the principal ketone body β-hydroxybutyrate in cardiomyocytes. Male BDH1cko and littermate controls underwent either permanent coronary artery ligation of the left anterior descending coronary artery to induce myocardial infarction (MI) or sham surgery. Two weeks after surgery, mice were randomized to 6 weeks of empagliflozin or vehicle treatment. Cardiac function was assessed using transthoracic echocardiography before and after treatment, and histological and molecular analyses were performed after sacrifice. Empagliflozin treatment resulted in a twofold increase in circulating ketone bodies. Mean infarct size (36 ± 4% of the left ventricle) was comparable among MI groups. In control mice, empagliflozin treatment resulted in a significant increase in left ventricular ejection fraction (LVEF) whereas LVEF remained stable in the vehicle treated group (ΔLVEF -1.1 ± 2.2% vs. 5.2 ± 1.5%, p < 0.05). Empagliflozin did not influence cardiac contractility in BDH1cko mice (ΔLVEF -5.9 ± 2.1% vs. -1.5 ± 2.8%, p = 0.213). Other echocardiographic, histological and molecular signatures of adverse myocardial remodelling were not affected by empagliflozin treatment.
CONCLUSION: The beneficial effects of empagliflozin on cardiac contractility in post-MI heart failure are attenuated in mice which are incapable of oxidizing the ketone body β-hydroxybutyrate in their hearts. These findings suggest that enhanced cardiac ketone body oxidation contributes to the cardioprotective effects of SGLT2i.

Keywords:  BDH1; Empagliflozin; Heart failure; Ketone bodies; Sodium–glucose cotransporter 2 inhibitors

DOI:  https://doi.org/10.1002/ejhf.3633
Int J Mol Sci. 2025 Feb 22. pii: 1887. [Epub ahead of print]26(5):

Sex-Specific Improvements in Myocardial Function and Angiogenesis with SGLT-2 Inhibitor Canagliflozin in a Swine Model of Metabolic Syndrome.

Dwight D Harris, Mark Broadwin, Christopher Stone, Sharif A Sabe, Meghamsh Kanuparthy, Ju-Woo Nho, Kelsey C Muir, M Ruhul Abid, Frank W Sellke.

  There is a significant body of literature to suggest that coronary artery disease (CAD) is a highly sex-specific disease. The study of sex-specific therapeutics and sex-specific responses to treatment for CAD remains underreported in the literature. Sodium-glucose transporter 2 (SGLT2) inhibitors are of growing interest in the treatment of ischemic heart disease and heart failure; however, the sex-specific response to SGLT2 inhibitors is unknown. We studied an SGLT2 inhibitor, canagliflozin, in a swine model of metabolic syndrome (MS) and chronic myocardial ischemia with emphasis on the sex-specific outcomes. Yorkshire swine (n = 21) were obtained at 6 weeks of age and fed a high-fat diet to induce MS. Left thoracotomy was performed on all swine at 11 weeks of age for the placement of an ameroid constrictor to model chronic myocardial ischemia. Swine recovered for two weeks, then were assigned to either the drug group, CAN 300 mg daily group (M = 5, F = 5), or the control group (CON, M = 5, F = 6). Both groups received 5 weeks of therapy. After completion of therapy, swine underwent functional assessment and terminal harvest. The male animals treated with CAN (CAN-M) had significant increases in stroke volume and cardiac output (p = 0.047, p < 0.001) compared to control males (CON-M), which were not seen in females treated with CAN (CAN-F) compared to control females (CON-F). Effective arterial elastance was decreased in CAN-M compared to CON-M. The CAN-F group had a significant increase in ischemic myocardial capillary density compared to CON-F (p = 0.04). There was no difference in capillary density between the CAN-M and CON-M groups. CAN treatment resulted in sex-specific changes in angiogenesis and myocardial function. The CAN-M group had significant improvements in cardiac function based on afterload reduction, stroke volume, and increased cardiac output not seen in the CAN-F group. The CAN-F group had increased ischemic myocardial capillary density. These findings provide a foundation for further investigation of the sex-specific effects of SGLT-2 inhibitors in humans.

Keywords:  ameroid constrictor; canagliflozin; chronic myocardial ischemia; female; male; metabolic syndrome; sex; sodium-glucose cotransporter-2 inhibitor

DOI:  https://doi.org/10.3390/ijms26051887
Int J Cardiol. 2025 Mar 09. pii: S0167-5273(25)00167-6. [Epub ahead of print]428 133124

Beyond the gut: Systemic levels of short-chain fatty acids are altered in patients with heart failure.

C L Palm, S de Wit, T M Gorter, M Rienstra, M J Vos, I P Kema, C P van der Ley, S J L Bakker, B M Bakker, R A de Boer, D J van Veldhuisen, W C Meijers, B D Westenbrink.

   BACKGROUND & AIM: The gut microbiome produces short-chain fatty acids (SCFAs), which serve as a substantial energy source and provide a link between the microbiome and (cardiac) metabolism. It has been demonstrated that the composition of the microbiome is altered in patients with heart failure (HF), but whether circulating levels of SCFAs are altered in HF is unknown.
METHODS & RESULTS: Serum concentrations of the SCFAs acetate, propionate, and butyrate were measured in 205 patients with HF and in 54 healthy controls, using isotope dilution liquid chromatography-tandem mass spectrometry. Of the patients with HF, 99 had HF with a reduced ejection fraction (HFrEF) and 106 had HF with mildly-reduced or preserved ejection fraction (HFmrEF/HFpEF). Healthy controls were age and sex matched to the HFrEF patients. Serum concentrations of acetate and propionate were significantly lower in patients with HF than in healthy controls, whereas butyrate levels were higher in patients with HF. Analyses by HF type revealed that acetate and propionate levels were lower in both HFrEF and HFpEF/HFmrEF patients in comparison to healthy controls. However, butyrate levels were observed to be lower in patients with HFmrEF/HFpEF in comparison to healthy controls, while they were higher in patients with HFrEF.
CONCLUSIONS: In patients with HF, serum levels of acetate and propionate are lower across the HF spectrum, whereas serum butyrate levels are elevated in HFrEF, but lower in HFmrEF/HFpEF. These alterations in SCFA profiles suggest a microbiome-driven metabolic dysregulation, which appears to differ between HF subtypes.

Keywords:  Heart failure; Metabolism; Microbiome; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.ijcard.2025.133124
ESC Heart Fail. 2025 Mar 10.

Association of plasma metabolites and cardiac mitochondrial function with heart failure progression.

Vandana Revathi Venkateswaran, Ruicong She, Stephen J Gardell, Jasmine A Luzum, Ramesh Gupta, Kefei Zhang, L Keoki Williams, Hani N Sabbah, David E Lanfear.

   AIMS: Plasma metabolites are prognostic in heart failure with reduced ejection fraction (HFrEF), with citric acid cycle metabolites linked to ejection fraction (EF) changes. We investigated these mechanisms in a canine chronic HFrEF model. We tested associations between changes in plasma metabolites, left ventricular (LV) end-diastolic volume and cardiomyocyte mitochondrial function.
METHODS: Eighteen dogs underwent microembolization to induce moderate HFrEF (target LVEF 35%-40%). Plasma metabolites, LV size and mitochondrial function were assessed over 12 months.
RESULTS: Plasma metabolite heatmap showed acylcarnitine changes, with early alterations in organic acids and amino acids predicting later adverse LV remodelling. Using either baseline or change over time, 13 metabolites correlated with 12 month LV enlargement. This is mostly often at 3 months (11 of 13), notably C18:2 (r = -0.58, P = 0.003) and cardiac anaplerotic substrates like glutamine (r = -0.52, P = 0.009) and 3-HBA (r = -0.43, P = 0.035). Impaired cardiomyocyte mitochondrial function correlated with LV enlargement (max ATP synthesis 12.7 vs. 19.9 nmol/min/mg, P = 0.0036; ADP-stimulated respiration 224 vs. 308 nAtom O/min/mg protein; P = 0.0064). Plasma metabolites correlated with mitochondrial parameters at 12 month, particularly with MAX ATP: malate (r = -0.75, P < 0.001), fumarate (r = -0.6, P = 0.008) and glutamine (r = 0.51, P = 0.031).
CONCLUSIONS: In canine HFrEF, plasma acylcarnitines, citric acid cycle or anaplerotic metabolites predicted adverse LV remodelling. LV enlargement correlated with reduced cardiomyocyte mitochondrial function, which in turn was also associated with increased citric acid cycle metabolites. Together, these data suggest impaired cardiac energetic function drives plasma metabolite associations in HFrEF progression.

Keywords:  cardiac mitochondrial progression; heart failure; plasma metabolite; plasma metabolomic profiling

DOI:  https://doi.org/10.1002/ehf2.15215
J Am Heart Assoc. 2025 Mar 13. e038945

Myocardial Proteome in Human Heart Failure With Preserved Ejection Fraction.

Vivek P Jani, Edwin J Yoo, Aleksandra Binek, Alina Guo, Julie S Kim, Jennifer Aguilan, Mohammad Keykhaei, Sydney R Jenkin, Simone Sidoli, Kavita Sharma, Jennifer E Van Eyk, David A Kass, Virginia S Hahn.

   BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all HF but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have identified major differences between HFpEF and controls. How this translates at the protein level is unknown.
METHODS AND RESULTS: Myocardial tissue from patients with HFpEF and nonfailing donor controls was analyzed by data-dependent acquisition (n=10 HFpEF, n=10 controls) and data-independent acquisition (n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Differential protein expression analysis, pathway overrepresentation, weighted coexpression network analysis, and machine learning were integrated with clinical characteristics and previously reported transcriptomics. Principal component analysis (data-dependent acquisition-mass spectrometry) found HFpEF separated into 2 subgroups: one similar to controls and the other disparate. Downregulated proteins in HFpEF versus controls were enriched in mitochondrial transport/organization, translation, and metabolism including oxidative phosphorylation. Proteins upregulated in HFpEF were related to immune activation, reactive oxygen species, and inflammatory response. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. Expression of oxidative phosphorylation and metabolism genes (higher) versus proteins (lower) was discordant in HFpEF versus controls. Data-independent acquisition-mass spectrometry proteomics also yielded 2 HFpEF subgroups; the one most different from controls had a higher proportion of patients with severe obesity and exhibited lower proteins related to fuel metabolism, oxidative phosphorylation, and protein translation. Three modules of correlated proteins in HFpEF that correlated with left ventricular hypertrophy and right ventricular load related to (1) proteasome; (2) fuel metabolism; and (3) protein translation, oxidative phosphorylation, and sarcomere organization.
CONCLUSIONS: Integrative proteomics, transcriptomics, and pathway analysis supports a defect in both metabolism and translation in HFpEF. Patients with HFpEF with more distinct proteomic signatures from control more often had severe obesity, supporting therapeutic efforts targeting metabolism and translation, particularly in this subgroup.

Keywords:  fatty acids; heart failure; metabolism; myocardium; obesity; oxidative phosphorylation; proteomics

DOI:  https://doi.org/10.1161/JAHA.124.038945