bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2026–03–08
six papers selected by
Kyle McCommis, Saint Louis University
  1. The metabolic balancing act between fatty acid and glucose substrate use for optimal myocardial function: Key role for membrane substrate transporters.
  2. Myocardial metabolic remodeling in human end-stage ischemic and non-ischemic cardiomyopathy.
  3. Transient elevation in cellular glucose uptake exacerbates pressure overload-induced cardiac hypertrophy and dysfunction.
  4. Metabolic therapy of cardiovascular diseases with propionyl L-carnitine.
  5. Nuclear AGO2 exacerbates heart failure with preserved ejection fraction through myocardial ketogenesis.
  6. Two-Hit Swine Model of Heart Failure With Preserved Ejection Fraction Mimics Cardiac and Systemic Pathologies.
  1. Am J Physiol Heart Circ Physiol. 2026 Mar 05.
    The metabolic balancing act between fatty acid and glucose substrate use for optimal myocardial function: Key role for membrane substrate transporters.
    Jan F C Glatz, Lisa C Heather, Terje S Larsen, Miranda Nabben, Joost J F P Luiken.
      Cardiac contractile function is strictly dependent on proper metabolic energy provision. Long-chain fatty acids and glucose are the primary energy substrates and are also indispensable for serving additional cellular roles including synthesis of biosynthetic precursors and post-translational modification of proteins. The balance between fatty acid and glucose utilization in the heart, and myocardial contractile function appear inextricably linked. A chronic shift towards a greater dependence on a single substrate, either fatty acids or glucose, results in a metabolic imbalance, and is associated with impaired cardiac function. As a result, re-balancing fatty acid and glucose utilization is an effective approach to restore cardiac contractile performance. In this article we discuss the significance of the fatty-acid-to-glucose fuel balance for maintaining homeostatic control, and show recent evidence that the membrane substrate transporters CD36 (for fatty acid uptake) and GLUT4 (for glucose uptake) are key targets to recover the myocardial substrate balance. In conclusion, the fatty acid-to-glucose substrate balance is both an effective target to treat heart failure and a useful parameter to monitor myocardial function in health and disease.
    Keywords:  cardiac function; cardiomyopathy; cellular glucose metabolism; cellular lipid metabolism; energy metabolism
    DOI:  https://doi.org/10.1152/ajpheart.00868.2025
  2. J Mol Cell Cardiol. 2026 Feb 26. pii: S0022-2828(26)00032-5. [Epub ahead of print]
    Myocardial metabolic remodeling in human end-stage ischemic and non-ischemic cardiomyopathy.
    Hongyi Zhou, Courtney Jayde Christopher, Katarina Jones, Michelle Mendiola Pla, Ryan T Gross, Gabriel Esmailian, Shawn Robert Campagna, Dawn E Bowles, Weiqin Chen.
       BACKGROUND: Heart failure (HF) is linked to disturbances in heart metabolism. Metabolomics shows promise in identifying cardiac-specific metabolic changes across different types of heart disease. However, direct comparison of metabolomic changes in myocardial tissues from humans with end-stage ischemic (ICM) and nonischemic (NICM) heart failure is scarce.
    METHODS: Left ventricles were collected from patients with end-stage ICM (n = 14) and NICM (n = 15), along with nonfailing donors (n = 11). Untargeted metabolomics assessed organic acids, amino acids, purines, and pyrimidines. Data were analyzed using partial least squares-discriminant analysis (PLS-DA), heat maps, Kruskal-Wallis with Dunn test, and ANOVA. RT-PCR and Western blotting were used to examine the expression of metabolic genes.
    RESULTS: Myocardial metabolites could distinguish diseased from nonfailing hearts; however, ICM and NICM samples often overlapped, despite ICM patients having higher rates of diabetes and hyperlipidemia. Glycolytic and TCA metabolites showed no differences within the groups. Notably, myocardial UDP-N-Acetyl-glucosamine and O-GlcNAcylation levels were consistently lower, despite increased expression of hexosamine pathway genes in both disease groups. Several amino acids decreased, yet branched-chain amino acids remained stable in ICM and NICM hearts. Both groups showed hyperhomocysteinemia and increased urea cycle intermediates. Glutathione (GSH) and glutathione disulfide (GSSG) levels were depleted regardless of glutathione synthesis gene expression. Adenylated purines and pyrimidines were reduced, with increased purine degradation and a notable upregulation of NC5E, an extracellular nucleotidase, in both disease groups. While ATP and NAD+ levels stayed relatively stable, NADH, FAD+, and NADP+ levels decreased in diseased hearts. Catalase was upregulated in both disease groups despite elevated markers of oxidative stress.
    CONCLUSION: Human end-stage heart failure is characterized by altered glucose and amino acid metabolism, heightened oxidative stress, increased purine breakdown, and reduced pyrimidine levels, with no differences observed between ischemic and nonischemic cardiomyopathy. These findings enhance our understanding of metabolic alterations in failing human hearts.
    Keywords:  Heart failure; Ischemic cardiomyopathy; Metabolomics; Nonischemic cardiomyopathy
    DOI:  https://doi.org/10.1016/j.yjmcc.2026.02.008
  3. Epigenetics. 2026 Dec;21(1): 2638670
    Transient elevation in cellular glucose uptake exacerbates pressure overload-induced cardiac hypertrophy and dysfunction.
    Sayan Bakshi, Samuel F Chang, Luke A Potter, Zhihuan Sun, Chae-Myeong Ha, Kerstin Preuss, Mahima S Reddy, Caitlin A Harrell, John C Chatham, Adam R Wende.
      Clinically prior hyperglycemia may lead to long-lasting adverse cardiovascular effects, a process referred to as 'glycemic memory.' Epigenetic modifications, specifically DNA methylation changes, may play a key role in this phenomenon. This study investigated if prior high glucose delivery to cardiomyocytes, led to worsened cardiovascular effects upon pressure overload and to ascertain the gene expression and corresponding DNA methylation signatures linked to glycemic memory. Using inducible and cardiomyocyte-specific glucose transporter 4 (GLUT4) overexpressing mice. We induced glucose delivery for 2 weeks, then returned to basal uptake for 2 weeks, followed by sham or transverse aortic constriction (TAC) surgery as a secondary stress. Mice were followed for an additional 8 weeks and assessed for contractile function, cellular remodeling, and molecular changes. TAC led to an exacerbated hypertrophic response and cardiac dysfunction in the transgenic mice. Subsequent analysis identified molecular changes akin to heart failure, worsened cardiac fibrosis, and oxidative stress. Using bulk RNA-sequencing and reduced representation bisulfite sequencing, we discovered differential gene expression and DNA methylation signatures that persisted even after cellular glucose levels reverted to normal. Significant changes across both expression and methylation-identified enriched pathways related to adverse cardiac events, supporting a glycemic memory response. Glycemic memory led to cardiac structural and functional exacerbation, mimicking heart failure, when subjected to a secondary stress. Our data identified transcriptome, and preliminary DNA methylome changes which may potentially be molecular signatures of future therapeutic targets associated with this heart failure susceptibility resulting from enhanced glucose delivery.
    Keywords:  Cardiomyopathy; DNA methylation; diabetes; gene expression; glycemic memory
    DOI:  https://doi.org/10.1080/15592294.2026.2638670
  4. Can J Physiol Pharmacol. 2026 Feb 28.
    Metabolic therapy of cardiovascular diseases with propionyl L-carnitine.
    Naranjan S Dhalla, Khushman Kaur, Vijayan Elimban, Paul Ganguly.
      Propionyl L-carnitine (PPLC), a short -chain fatty acid derivative of carnitine, has been reported to produce beneficial effects in various cardiovascular diseases such as maladaptive cardiac hypertrophy, heart failure, ischemic heart disease, different types of cardiomyopathies and peripheral artery disease. Although all these cardiovascular diseases have diverse epidemiology and pathophysiology, both clinical and preclinical studies have indicated the role of oxidative stress, Ca2+-handling defects and metabolic abnormalities in their development and progression. In heart failure due to myocardial infarction, treatment with PPLC attenuated the inhibition of Na+-K+ ATPase and Na+-Ca2+ exchange activities. PPLC therapy of animals with diabetic cardiomyopathy improved Ca2+- handling abnormalities in cardiomyocytes by affecting the entry of Ca2+ through sarcolemma and regulating the sarcoplasmic reticular Ca2+- pump activities. The improvement of cardiac function recovery by PPLC treatment in ischemia- reperfused hearts was associated with its ability to antagonize the deleterious effects of palmitoyl L-carnitine on Ca2+-handling proteins. Treatment of peripheral artery disease with PPLC increased blood flow by affecting the vascular endothelium and smooth muscle functions in lower limbs. These observations support the view that PPLC improves cardiovascular function in diseased conditions by promoting mitochondrial metabolism, reducing oxidative stress and preventing Ca2+- handling abnormalities.
    DOI:  https://doi.org/10.1139/cjpp-2025-0241
  5. Eur Heart J. 2026 Mar 05. pii: ehag067. [Epub ahead of print]
    Nuclear AGO2 exacerbates heart failure with preserved ejection fraction through myocardial ketogenesis.
    Kunying Jin, Yuyan Tang, Jiabing Zhan, Yufei Zhou, Rong Xie, Guo Hu, Yatong Qin, Jianpei Wen, Zheng Wen, Yanru Zhao, Jiahui Fan, Hengzhi Du, Feng Wang, Suzhen Tang, Shaowen Yang, Yusong R Guo, Dawei Jiang, Junfang Wu, Qian Liu, Xiang Cheng, Huaping Li, Chen Chen.
       BACKGROUND AND AIMS: With the prevalence of Western-style high-fat diet (HFD), the incidence of heart failure with preserved ejection fraction (HFpEF) is gradually increasing. Recent studies suggested that microRNAs (miRNAs) located in different subcellular organelles could regulate lipid metabolism and cardiac function. However, the functional property of subcellular argonaute 2 (AGO2), the core member of miRNA machinery, remained elusive in HFD-related HFpEF.
    METHODS: The causal role of nuclear AGO2 in inducing cardiac dysfunction was revealed with a recombinant adeno-associated virus (serotype 9) vector. The underlying mechanisms were explored with echocardiography, catheter manometer system, proteomics analyses, chromatin immunoprecipitation assays, luciferase assays, Western blotting, immunofluorescence, seahorse assays, β-hydroxybutyrate (β-OHB), and ATP measurements.
    RESULTS: Knockdown of AGO2 attenuated HFD-induced cardiac dysfunction. Mechanistically, AGO2 could activate the transcription of HMGCS2. Knockdown of either cardiac AGO2 or HMGCS2 protected against HFD-induced cardiac dysfunction. Subsequent high-through profiling further identified ATP5MG and UQCR10 as the key downstream targets for AGO2/HMGCS2 mediated β-OHB over-production, and a feed forward loop involving lipo-toxicity and ketone-toxicity was discovered. Furthermore, a PKCα-ERK-EGR1-AGO2-HMGCS2 axis in the initiation of fatty acid-induced cardiomyocyte dysfunction was revealed. Importantly, overexpressing of nuclear AGO2 rather than cytosolic AGO2 exacerbated the HFD-induced cardiac dysfunction in mice.
    CONCLUSIONS: These findings uncover that long-term Western-style HFD treatment captures some critical characteristics of HFpEF, characterized by diastolic dysfunction with left ventricular ejection fraction >50%. AGO2/HMGCS2 pathway links lipo-toxicity to ketone-toxicity in the heart, which provides new mechanistic insights and suggests a potential strategy to develop treatments against metabolism disorder-related HFpEF.
    Keywords:  AGO2; Heart failure with preserved ejection fraction; Ketone body; Lipo-toxicity; Nuclear
    DOI:  https://doi.org/10.1093/eurheartj/ehag067
  6. JACC Asia. 2025 Dec 01. pii: S2772-3747(25)00593-9. [Epub ahead of print]
    Two-Hit Swine Model of Heart Failure With Preserved Ejection Fraction Mimics Cardiac and Systemic Pathologies.
    Myu Mai Ja Kp, Shuo Cong, Fan Yu, Song Yi Ron Lim, Francis Hong Xin Yap, Philip Wong, Chrishan J Ramachandra, Derek J Hausenloy.
       BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of heart failure cases and is associated with significant morbidity and mortality. Developing preclinical models that recapitulate the cardiac and systemic pathologies of HFpEF is critical for advancing treatment.
    OBJECTIVES: Large animal models offer translational relevance due to physiological similarities to humans, but few capture both cardiac and extracardiac features of HFpEF. The authors aimed to develop a swine model of HFpEF using a 2-hit intervention combining high-salt diet with infrarenal aortic banding.
    METHODS: Female swine were subjected to this intervention and evaluated longitudinally over 20 weeks. Echocardiography and invasive pressure-volume (PV) loop analysis assessed cardiac remodeling and diastolic dysfunction. Histopathology was performed on cardiac and extracardiac tissues, including lungs, liver, and kidneys.
    RESULTS: The 2-hit intervention induced a progressive HFpEF phenotype over 20 weeks, as evidenced by echocardiographic increases in left ventricular mass, wall thickness, left atrial volume, and diastolic dysfunction with preserved systolic function. PV loop analysis revealed a steeper end-diastolic PV relationship, indicating increased left ventricular stiffness and reduced compliance. Histology showed early myocardial fibrosis at 4 weeks, with atrial-to-ventricular progression of cardiomyocyte hypertrophy culminating in global cardiac hypertrophy by 20 weeks. Extracardiac findings included pulmonary and hepatic congestion with associated structural remodeling and fibrosis, and renal remodeling accompanied by elevated serum creatinine, consistent with systemic HFpEF pathophysiology.
    CONCLUSIONS: This novel 2-hit swine model replicates key cardiac and systemic pathologies of human HFpEF and provides a robust platform for elucidating underlying mechanisms and evaluating potential therapies.
    Keywords:  diastolic dysfunction; fibrosis; heart failure with preserved ejection fraction; large animal model; systemic pathology; tissue remodeling
    DOI:  https://doi.org/10.1016/j.jacasi.2025.10.014
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