bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2025–04–27
twelve papers selected by
Kyle McCommis, Saint Louis University
  1. Cardiac Energy Substrate Utilization in Heart Failure with Preserved Ejection Fraction: Reconciling Conflicting Evidence on Fatty Acid and Glucose Metabolism.
  2. Ketone therapy improves cardiac function and structure in rodents with heart failure: A systematic review and meta-analysis.
  3. Fatty acids in heart failure patients: friend or foe?
  4. Impact of Cholesterol on Cardiac Mitochondrial Function.
  5. Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.
  6. Novel Molecules Targeting Metabolism and Mitochondrial Function in Cardiac Diseases.
  7. Alpha-7 nicotinic and muscarinic acetylcholine receptor agonists promote a favorable pattern of cardiac metabolic reprogramming in doxorubicin-induced heart failure rats.
  8. Tirzepatide for Heart Failure and Obesity.
  9. Tirzepatide for Heart Failure and Obesity.
  10. Tirzepatide for Heart Failure and Obesity.
  11. Tirzepatide for Heart Failure and Obesity. Reply.
  12. Tirzepatide for Heart Failure and Obesity.
  1. Am J Physiol Heart Circ Physiol. 2025 Apr 18.
    Cardiac Energy Substrate Utilization in Heart Failure with Preserved Ejection Fraction: Reconciling Conflicting Evidence on Fatty Acid and Glucose Metabolism.
    Lina A Shehadeh, Emely Robleto, Gary D Lopaschuk.
      Heart failure with preserved ejection fraction (HFpEF) is characterized by complex metabolic derangements, yet considerable controversy exists regarding the role, and specifically the direction, of fatty acid oxidation (FAO) in disease progression. Through a systematic review with narrative synthesis of 44 studies identified from MEDLINE, Embase, and Web of Science databases, we critically examine the seemingly contradictory evidence regarding cardiac FAO in HFpEF. Our systematic analysis of experimental approaches reveals that many apparent contradictions can be resolved by considering differences in methodological approaches, interpretation of indirect metabolic markers, and the dynamic nature of metabolic adaptation in disease progression. Direct measurements consistently demonstrate that FAO remains active or increased in HFpEF hearts while glucose oxidation becomes impaired, challenging previous assumptions based on indirect metabolic assessments. Methodological differences, particularly between studies using isolated mitochondria versus intact hearts and indirect versus direct substrate utilization measurements, can explain many apparent contradictions in the literature. Clinical and experimental evidence supports that FAO is maintained or elevated in HFpEF, with primary defects occurring in glucose oxidation and mitochondrial quality control. These findings suggest that successful therapeutic strategies for HFpEF should prioritize restoring metabolic flexibility and optimizing substrate utilization patterns rather than simply modulating FAO pathways. Our synthesis of the literature provides a comprehensive framework for understanding cardiac energy metabolism in HFpEF and identifies critical areas for future investigation.
    Keywords:  Cardiac Energy Metabolism; Fatty Acid Oxidation (FAO); Heart Failure with Preserved Ejection Fraction (HFpEF); Metabolic Flexibility; Mitochondrial Function
    DOI:  https://doi.org/10.1152/ajpheart.00121.2025
  2. Nutr Res. 2025 Mar 26. pii: S0271-5317(25)00043-0. [Epub ahead of print]137 56-70
    Ketone therapy improves cardiac function and structure in rodents with heart failure: A systematic review and meta-analysis.
    Tingting Lv, Chunyan Liu, Mengfei Ye, Gang Li, Zheng Liu.
      This meta-analysis aimed to quantitatively assess the effects of ketone intervention on cardiac function and structure in rodents with heart failure (HF). We hypothesized that ketone intervention could enhance the cardiac function and structure in HF. We systematically searched PubMed, Cochrane Library, and Embase databases for relevant studies up to April 13, 2024. Ketone therapy encompassed a ketogenic diet, ketone esters, medium-chain triglycerides, and β-hydroxybutyrate. The effect measures are mainly expressed as standardized mean difference (SMD) and 95% confidence interval (CI). Our meta-analysis included 24 animal studies. Ketone therapy significantly improved left ventricular ejection fraction (SMD: 1.31, 95% CI: 0.79-1.82, I2 = 77%), cardiac output (SMD: 0.70, 95% CI: 0.28-1.11, I2 = 0%), and ameliorated myocardial hypertrophy (SMD: -1.95, 95% CI: -2.76 to -1.13, I2 = 76%), myocardial fibrosis (SMD: -0.87, 95% CI: -1.60 to -0.15, I2 = 68%), and ventricular remodeling in HF rodents. Subgroup analysis indicated that ketone intervention worsened myocardial fibrosis in non-HF rodents (SMD: 0.86, 95% CI: 0.09-1.63, I2 = 78%) and had no significant effect on cardiac function. Additionally, further subgroup analysis indicated that ketogenic diet significantly alleviated cardiac hypertrophy and fibrosis, whereas ketone esters did not yield significant effects. The effect of ketone on left ventricular ejection fraction strengthened with the duration of intervention. Our results suggested that ketone therapy significantly improved the cardiac systolic function and structure in rodents with HF, and had no effect in rodents non-HF. Thus, ketone intervention may be a promising treatment for HF patients.
    Keywords:  Cardiac function and structure; Heart failure; Ketone intervention; Mechanism; Meta-analysis; Rodents
    DOI:  https://doi.org/10.1016/j.nutres.2025.03.008
  3. Eur Heart J. 2025 Apr 25. pii: ehaf247. [Epub ahead of print]
    Fatty acids in heart failure patients: friend or foe?
    Henrik Wiggers.
      
    DOI:  https://doi.org/10.1093/eurheartj/ehaf247
  4. Circ Res. 2025 Apr 25. 136(9): 943-945
    Impact of Cholesterol on Cardiac Mitochondrial Function.
    Gary D Lopaschuk.
      
    Keywords:  Editorials; cholesterol; heart failure; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326464
  5. Cell Metab. 2025 Apr 18. pii: S1550-4131(25)00211-6. [Epub ahead of print]
    Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.
    Yuki Tatekoshi, Amir Mahmoodzadeh, Jason S Shapiro, Mingyang Liu, George M Bianco, Ayumi Tatekoshi, Spencer Duncan Camp, Adam De Jesus, Navid Koleini, Santiago De La Torre, J Andrew Wasserstrom, Wolfgang H Dillmann, Benjamin R Thomson, Kenneth C Bedi, Kenneth B Margulies, Samuel E Weinberg, Hossein Ardehali.
      Heart failure with preserved ejection fraction (HFpEF) is a common cause of morbidity and mortality worldwide, but its pathophysiology remains unclear. Here, we report a mouse model of HFpEF and show that hexokinase (HK)-1 mitochondrial binding in endothelial cells (ECs) is critical for protein O-GlcNAcylation and the development of HFpEF. We demonstrate increased mitochondrial dislocation of HK1 within ECs in HFpEF mice. Mice with deletion of the mitochondrial-binding domain of HK1 spontaneously develop HFpEF and display impaired angiogenesis. Spatial proximity of dislocated HK1 and O-linked N-acetylglucosamine transferase (OGT) causes increased OGT activity, shifting the balance of the hexosamine biosynthetic pathway intermediates into the O-GlcNAcylation machinery. EC-specific overexpression of O-GlcNAcase and an OGT inhibitor reverse angiogenic defects and the HFpEF phenotype, highlighting the importance of protein O-GlcNAcylation in the development of HFpEF. Our study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation, and provides a potential therapy for HFpEF.
    Keywords:  HFpEF; O-GlcNAcylation; endothelial cell; hexokinase 1; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.001
  6. Curr Cardiol Rev. 2025 Apr 18.
    Novel Molecules Targeting Metabolism and Mitochondrial Function in Cardiac Diseases.
    Samir Bolivar Gonzalez, César Vásquez Trincado, Karen Patricia Torres Rodríguez, Lizeth Paola Forero Acosta, Maria Fernanda Perez García, Steffy Saavedra Castro, Sara Camila Castiblanco Arroyave, Gerardo Manríquez Higuera, Luis Antonio Díaz Ariza, Héctor Rodríguez Ortiz, Evelyn Mendoza-Torres.
      Cardiovascular diseases (CVD) are the leading cause of death worldwide, creating the need for new therapeutic strategies targeting the pathological processes involved. Mitochondria, which comprise one-third of cardiac cell volume, maybe a potential therapeutic target for CVD. Known primarily for energy production, mitochondria are also involved in other processes including intermediary metabolism, mitophagy, calcium homeostasis, and regulation of cell apoptosis. Mitochondrial function is closely linked to morphology, which is altered through mitochondrial dynamics, including processes such as fission and fusion, which ensure that the energy needs of the cell are met. Recent data indicate that mitochondrial dysfunction is involved in the pathophysiology of several CVDs, including cardiac hypertrophy, heart failure, ischemia/reperfusion injury, and cardiac fibrosis. Furthermore, mitochondrial dysfunction is associated with oxidative stress related to atherosclerosis, hypertension, and pulmonary hypertension. In this review, we first briefly present the physiological mechanisms of mitochondrial function in the heart and then summarize the current knowledge on the impact of mitochondrial dysfunction on CVD. And finally, we highlight the evidence from in vitro, in vivo, and clinical studies of the cardioprotective effects of drugs that preserve mitochondrial function in CVD. It is hoped that this review may provide new insights into the need to discover new pharmacological targets with direct actions on mitochondria that may provide combined therapeutic strategies to optimally treat these pathologies.
    Keywords:  Cardiovascular disease; angiotensins; cardiac hypertrophy; heart failure; ischemia; metformin; mitochondrial dynamics; nicotinamide riboside.
    DOI:  https://doi.org/10.2174/011573403X372565250331190001
  7. Arch Biochem Biophys. 2025 Apr 17. pii: S0003-9861(25)00140-7. [Epub ahead of print] 110427
    Alpha-7 nicotinic and muscarinic acetylcholine receptor agonists promote a favorable pattern of cardiac metabolic reprogramming in doxorubicin-induced heart failure rats.
    Chanisa Thonusin, Thawatchai Khuanjing, Wichwara Nawara, Siriporn C Chattipakorn, Nipon Chattipakorn.
      Sympathetic hyperactivation and metabolic reprogramming are found in heart failure. Parasympathetic activation by acetylcholine receptor agonists attenuates doxorubicin-induced heart failure by improving mitochondrial function and ameliorating apoptosis and inflammation. However, the effect of these agents on cardiac metabolic reprogramming in doxorubicin-induced heart failure has never been investigated. Male Wistar rats received either vehicle, 6 doses of 3 mg/kg/day of doxorubicin, 6 doses of 3 mg/kg/day of doxorubicin and 3 mg/kg/day of an alpha-7 nicotinic acetylcholine receptor agonist for 30 days, or 6 doses of 3 mg/kg/day of doxorubicin and 12 mg/kg/day of a muscarinic acetylcholine receptor agonist for 30 days. Then, the rats were euthanized to collect heart and serum for metabolomics study. Doxorubicin caused increased glycolysis, increased ketone body utilization, decreased fat utilization, decreased succinate oxidation, and decreased adenosine triphosphate production. Co-treatment with acetylcholine receptor agonist ameliorated an increase in glycolysis, and restored fat utilization, succinate oxidation, and adenosine triphosphate production in the heart. Metabolome alterations in serum were consistent with those in the heart. Our findings highlighted the roles of metabolomics in identifying cardiac metabolic reprogramming and emphasized the potential of acetylcholine receptor agonist in promoting a favorable pattern of cardiac metabolic reprogramming in doxorubicin-induced heart failure.
    Keywords:  Acetylcholine receptor agonist; Doxorubicin; Energy metabolism; Heart failure; Metabolic reprogramming; Parasympathetic activation
    DOI:  https://doi.org/10.1016/j.abb.2025.110427
  8. N Engl J Med. 2025 Apr 24. pii: 10.1056/NEJMc2502743#sa4. [Epub ahead of print]392(16): 1661
    Tirzepatide for Heart Failure and Obesity.
    M Kasim Ali.
      
    DOI:  https://doi.org/10.1056/NEJMc2502743
  9. N Engl J Med. 2025 Apr 24. pii: 10.1056/NEJMc2502743#sa1. [Epub ahead of print]392(16): 1659-1660
    Tirzepatide for Heart Failure and Obesity.
    Jeffrey Wagner.
      
    DOI:  https://doi.org/10.1056/NEJMc2502743
  10. N Engl J Med. 2025 Apr 24. pii: 10.1056/NEJMc2502743#sa3. [Epub ahead of print]392(16): 1660
    Tirzepatide for Heart Failure and Obesity.
    Joseph E Marine, John Mandrola, Vinay Prasad.
      
    DOI:  https://doi.org/10.1056/NEJMc2502743
  11. N Engl J Med. 2025 Apr 24. pii: 10.1056/NEJMc2502743#sa5. [Epub ahead of print]392(16): 1661-1662
    Tirzepatide for Heart Failure and Obesity. Reply.
    Milton Packer, Christopher M Kramer, Barry A Borlaug.
      
    DOI:  https://doi.org/10.1056/NEJMc2502743
  12. N Engl J Med. 2025 Apr 24. pii: 10.1056/NEJMc2502743#sa2. [Epub ahead of print]392(16): 1660
    Tirzepatide for Heart Failure and Obesity.
    Jesse C Krakauer, Nir Y Krakauer.
      
    DOI:  https://doi.org/10.1056/NEJMc2502743
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