bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2025–11–02
seven papers selected by
Kyle McCommis, Saint Louis University
  1. Ketone Catabolism Is Essential for Maintaining Normal Heart Function During Aging.
  2. The crosstalk between mitochondrial dysfunction and fatty acid metabolism in heart failure: mechanisms and therapeutic strategies.
  3. Systemic Metabolic Rewiring in a Mouse Model of Left Ventricular Hypertrophy.
  4. Mitochondrial Dysfunction Contributes to Decompensation in a Zebrafish Model of Isoproterenol-Induced Heart Failure.
  5. Unlocking metabolic flexibility in heart failure with preserved ejection fraction: Bridging fundamental mechanisms to clinical innovation.
  6. Pyruvate Dehydrogenase Complex Stimulation with Dichloroacetate May Improve Septic Cardiac Dysfunction.
  7. GLP-1 Receptor Agonists in Heart Failure.
  1. J Am Heart Assoc. 2025 Oct 28. e042508
    Ketone Catabolism Is Essential for Maintaining Normal Heart Function During Aging.
    Mariko Aoyagi Keller, Michinari Nakamura.
       BACKGROUND: The heart uses various nutrient sources for energy production, primarily favoring fatty acid oxidation. Although ketones can be fuel substrates, ketolysis has been shown to be dispensable for heart development and function in mice. However, the long-term consequences of ketolysis downregulation in the heart remain unknown. Here we demonstrate that ketone catabolism is essential for preserving cardiac function during aging.
    METHODS: To investigate the functional significance of ketone use in the heart, we employed a mouse model with impaired ketolysis in the heart. In addition, we administered a ketogenic diet to evaluate the effects of exogenous ketone supplementation on cardiac ketone metabolism and function in this model.
    RESULTS: The cardiac expression of SCOT (succinyl-CoA:3-ketoacid CoA transferase), a rate-limiting enzyme in ketolysis, decreases with age in mice. SCOT cardiomyocyte-specific knockout mice exhibit normal heart function at 10 weeks of age but progressively develop cardiac dysfunction and remodeling as they age, without overt hypertrophy in both sexes. Notably, ketone supplementation via a ketogenic diet partially rescues contractile dysfunction in SCOT cardiomyocyte-specific knockout mice, suggesting ketone oxidation-independent mechanisms contribute to the development of cardiomyopathy caused by SCOT downregulation.
    CONCLUSIONS: These findings indicate that ketone catabolism is crucial for maintaining heart function during aging, and that ketones confer cardioprotection independently of ketone oxidation.
    Keywords:  cardiac remodeling; heart failure; hypertrophy; ketogenic diet; ketolysis; ketone; ketone oxidation
    DOI:  https://doi.org/10.1161/JAHA.125.042508
  2. Front Pharmacol. 2025 ;16 1679085
    The crosstalk between mitochondrial dysfunction and fatty acid metabolism in heart failure: mechanisms and therapeutic strategies.
    Min Wang, Zheqin Zhu, Xuan He, Sisi Dai, Rongzhen Liu, Jianhe Liu.
      Heart failure is characterized by progressive energetic insufficiency, in which mitochondrial dysfunction and impaired fatty acid oxidation are central features. Normally, the FAO provides most of the cardiac ATP supply, but in HF, this pathway becomes disrupted, leading to the accumulation of lipid intermediates, oxidative stress, and reduced ATP production. Emerging evidence suggests that mitochondrial impairment and FAO disturbances may interact reciprocally, forming a vicious cycle that aggravates energetic failure and structural remodeling. This review summarizes current knowledge on the bidirectional relationship between mitochondrial dysfunction and FAO abnormalities in HF. We integrate findings from experimental models with clinical observations that highlight the translational relevance of this interplay. In addition, we provide an updated overview of therapeutic strategies, including pharmacological modulators such as SGLT2 inhibitors and trimetazidine, as well as traditional Chinese medicine formulas such as Qiliqiangxin and Qishen granules, which have shown preliminary benefits in clinical studies. Although the proposed vicious cycle remains a working hypothesis requiring further validation, understanding this interplay may help identify novel biomarkers, stratify patients by metabolic phenotype, and guide precision therapies for HF.
    Keywords:  energy metabolism; fatty acid oxidation; heart failure; mitochondrial dysfunction; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fphar.2025.1679085
  3. Int J Mol Sci. 2025 Oct 17. pii: 10111. [Epub ahead of print]26(20):
    Systemic Metabolic Rewiring in a Mouse Model of Left Ventricular Hypertrophy.
    Alexandra V Schmidt, Tharika Thambidurai, Olivia D'Annibale, Sivakama S Bharathi, Tim Wood, Eric S Goetzman, Julian E Stelzer.
      Left ventricular hypertrophy (LVH) refers to the pathological thickening of the myocardial wall and is strongly associated with several adverse cardiac outcomes and sudden cardiac death. While the biomechanical drivers of LVH are well established, growing evidence points to a critical role for cardiac and systemic metabolism in modulating hypertrophic remodeling and disease pathogenesis. Despite the efficiency of fatty acid oxidation (FAO), LVH hearts preferentially increase glucose uptake and catabolism to drive glycolysis and oxidative phosphorylation (OXPHOS). The development of therapies to increase and enhance LFCA FAO is underway, with promising results. However, the mechanisms of systemic metabolic states and LCFA dynamics in the context of cardiac hypertrophy remain incompletely understood. Further, it is unknown to what extent cardiac metabolism is influenced by whole-body energy balance and lipid profiles, despite the common occurrence of lipotoxicity in LVH. In this study, we measured whole-body and cellular respiration along with analysis of lipid and glycogen stores in a mouse model of LVH. We found that loss of the cardiac-specific gene, myosin-binding protein C3 (Mybpc3), resulted in depletion of adipose tissue, decreased mitochondrial function in skeletal muscle, increased lipid accumulation in both the heart and liver, and loss of whole-body metabolic flux. We found that supplementation of exogenous LCFAs boosted LVH mitochondrial function and reversed cardiac lipid accumulation but did not fully reverse the hypertrophied heart nor systemic metabolic phenotypes. This study indicates that the LVH phenotype caused systemic metabolic rewiring in Mybpc3-/- mice and that exogenous LCFA supplementation boosted mitochondrial function in both cardiac and skeletal muscle.
    Keywords:  cardiac lipotoxicity; cardiac myosin-binding protein C; left ventricular hypertrophy; long-chain fatty acid; systemic metabolism
    DOI:  https://doi.org/10.3390/ijms262010111
  4. Acta Physiol (Oxf). 2025 Dec;241(12): e70128
    Mitochondrial Dysfunction Contributes to Decompensation in a Zebrafish Model of Isoproterenol-Induced Heart Failure.
    Manuel Vicente, Aaron García-Blázquez, Antonio Martínez-Sielva, Jussep Salgado-Almario, Joaquín Jordán, Beatriz Domingo, Juan Llopis.
       AIM: Heart failure is a clinical syndrome where the heart's structural or functional impairment leads to inadequate blood flow to meet the body's metabolic demands. Mitochondrial dysfunction is increasingly recognized as a central contributor underlying the contractile impairment observed in the failing heart. This study aimed to explore the interplay between calcium dynamics, cardiac mechanical performance, and mitochondrial ATP production during the progression of heart failure in zebrafish larvae exposed to chronic isoproterenol stimulation.
    METHODS: Heart failure was induced by treating zebrafish larvae with 100 μM isoproterenol from 3 to 14 days postfertilization (dpf). Cardiac calcium transients, contractility, and mitochondrial ATP levels were assessed in vivo using transgenic lines expressing specific fluorescent biosensors. Additionally, transcriptomic analysis by RNA sequencing was performed on hearts collected at 14 dpf following prolonged isoproterenol exposure.
    RESULTS: After 4 days of isoproterenol treatment (7 dpf), larvae exhibited ventricular dilation, reduced calcium levels, and diminished contractile force (p < 0.0001), although cardiac output remained intact. In contrast, extended treatment (11 days; 14 dpf) led to decompensated heart failure, characterized by a significant decline in cardiac output (p < 0.0001). Mitochondrial ATP levels were preserved at 7 dpf but dropped markedly at 14 dpf (p < 0.0001). Transcriptomic profiling at this later stage revealed downregulation of key functions (p < 0.05) involved in mitochondrial energy metabolism and energy transfer.
    CONCLUSION: In this model, heart dysfunction was initially evidenced by cardiac dilation. At 4 days of isoproterenol treatment, calcium levels and contractility decreased. Subsequently, decompensation coincided with a collapse in mitochondrial ATP production.
    Keywords:  ATP; calcium; heart failure; mitochondria; transcriptomics; zebrafish
    DOI:  https://doi.org/10.1111/apha.70128
  5. iScience. 2025 Oct 17. 28(10): 113471
    Unlocking metabolic flexibility in heart failure with preserved ejection fraction: Bridging fundamental mechanisms to clinical innovation.
    Junyan Xia, Yibing Nong, Jun Teng, Shafeeq A Mohammed, Jing Liu, Yanting Pang, Sarah Costantino, Frank Ruschitzka, Nazha Hamdani, Mahmoud Abdellatif, Qian Lin, Francesco Paneni.
      Heart failure is often described as a condition of "energy depletion." However, in heart failure with preserved ejection fraction (HFpEF), particularly when associated with metabolic conditions such as obesity and diabetes, the heart may face a state of fuel overload. This fuel overload disrupts mitochondrial function, leading to the heart's inability to effectively adjust substrate utilization in response to variations in nutritional status, energy substrate availability, and hemodynamic load, resulting in loss of metabolic flexibility and subsequent adverse effects on cardiac function and structure. Thus, an in-depth analysis of the role of metabolic flexibility in the pathophysiology of HFpEF could pave the way to addressing this clinical challenge. This review addresses: (1) the alterations in metabolic flexibility observed in cardiometabolic disease and HFpEF; (2) the implications of metabolic flexibility in the staging, classification, diagnosis, and prognosis of HFpEF; and (3) current HFpEF therapeutic strategies that improve myocardial metabolic flexibility.
    Keywords:  Cardiovascular medicine; Human metabolism; Metabolic flux analysis
    DOI:  https://doi.org/10.1016/j.isci.2025.113471
  6. Shock. 2025 Oct 31.
    Pyruvate Dehydrogenase Complex Stimulation with Dichloroacetate May Improve Septic Cardiac Dysfunction.
    Lane M Smith, Yu Tin Lin, Chelsey S Mertens, Manal L Zabalawi, David L Long, Barbara K Yoza, Anderson O Cox, Boone M Prentice, Peter W Stacpoole, Charles E McCall.
       BACKGROUND: Cardiomyopathy is a common complication of sepsis that contributes to increased morbidity and mortality. However, the molecular mechanisms underlying septic cardiomyopathy are poorly understood. Dichloroacetate (DCA) improves mitochondrial respiration and survival in a mouse model of sepsis by inhibiting pyruvate dehydrogenase kinase which inactivates pyruvate dehydrogenase (PDH) through phosphorylation of its subunits. In this study, we explore the role of DCA in septic cardiac dysfunction using a murine sepsis model.
    METHODS: Cecal ligation and puncture (CLP) was performed in mice to investigate molecular and echocardiographic response to sepsis. DCA was administered to test the effects of PDH activation on cardiac performance during early and late sepsis and myocardial metabolic substrate production. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry was used to reveal spatial alterations in metabolism.
    RESULTS: CLP significantly increased phosphorylation of the PDH E1α subunit (PDH inactivation), and DCA treatment reduced PDH E1α phosphorylation (PDH activation) to baseline without affecting total PDH E1α levels. Administration of DCA at the time of CLP improved cardiac preload and stroke volume without affecting cardiac contractility at 12 h after CLP. However, there was a significant increase in cardiac contractility at 30 h after DCA administration independent of cardiac loading conditions. This improved cardiac function after DCA administration was associated with a trend toward decreased production of metabolic intermediates such as ketogenic amino acids, succinate, and palmitoyl carnitine. Imaging mass spectrometry revealed an increase in itaconate expression upon CLP that was mitigated by DCA administration.
    CONCULSIONS: Our findings revealed that sepsis decreased PDH activity in cardiac tissue. Rebalancing PDH activity with DCA improved cardiac performance after CLP. While imaging mass spectrometry identified changes in itaconate concentration and enabled detection of tricarboxylic acid cycle metabolites, further investigation is necessary to determine whether DCA is an effective therapeutic agent for septic cardiomyopathy.
    Keywords:  Cardiomyopathy; infection; inflammation; metabolism; shock
    DOI:  https://doi.org/10.1097/SHK.0000000000002642
  7. Biomolecules. 2025 Oct 02. pii: 1403. [Epub ahead of print]15(10):
    GLP-1 Receptor Agonists in Heart Failure.
    Ali Reza Rahmani, Simrat Kaur Dhaliwal, Paola Pastena, Eliot Kazakov, Keerthana Jayaseelan, Andreas Kalogeropoulos.
      Heart failure (HF) is a growing public health concern, driven by the increasing prevalence of obesity, diabetes, and aging. Despite therapeutic advances, HF continues to be associated with high morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for glycemic control in type 2 diabetes, have demonstrated cardiovascular benefits in clinical trials. Recent studies, including STEP-HFpEF and SUMMIT, have shown improvement in symptoms and weight loss in patients with HF with preserved ejection fraction (HFpEF). GLP-1 RAs are involved in multiple biological pathways relevant to heart failure pathophysiology. These include pathways related to sympathetic nervous system activity, inflammatory cytokine signaling, oxidative stress, calcium handling, natriuretic peptide signaling, and cardiac metabolism. GLP-1 receptor agonists modulate vascular pathways involving nitric oxide signaling, endothelial function, and renal sodium handling, contributing to improved hemodynamics and neurohormonal balance. Together, these actions intersect with key neurohormonal and cellular processes contributing to chronic heart failure progression. This review explores the mechanistic overlap between GLP-1 receptor signaling and heart failure pathophysiology. This mechanistic overlap suggests a plausible role for these agents as adjunctive treatments in heart failure, especially in metabolically driven phenotypes. While direct cardiac effects remain incompletely defined, systemic metabolic and anti-inflammatory actions provide a mechanistic basis for observed clinical benefits.
    Keywords:  GLP-1 RAs; heart failure; molecular pathways; pathophysiology
    DOI:  https://doi.org/10.3390/biom15101403
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒03 at 14:37.