bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2026–06–28
six papers selected by
Kyle McCommis, Saint Louis University
  1. AMPK Signalling in Heart Failure: From Metabolic Sensor to Context-Dependent Therapeutic Target.
  2. SGLT2 Inhibitors in Hypertrophic Cardiomyopathy: Emerging Evidence and Putative Mechanisms.
  3. Stiffness-induced impairment of GLUT4 trafficking in adult cardiomyocytes.
  4. Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.
  5. Protein phosphatase 2A impairs cardiac uptake of glucose in the mammalian heart.
  6. Determinants of Adherence to a Ketogenic Diet in Patients with Heart Failure with Reduced Ejection Fraction.
  1. Biomedicines. 2026 Jun 17. pii: 1362. [Epub ahead of print]14(6):
    AMPK Signalling in Heart Failure: From Metabolic Sensor to Context-Dependent Therapeutic Target.
    Rayan Arzouni, Reem Aazar, Seif Asakrieh, Seif Cattan, Aleksandar Jovanović.
      Heart failure (HF) is a complex clinical syndrome characterized not only by impaired cardiac function but also by profound disturbances in myocardial energy metabolism. AMP-activated protein kinase (AMPK), a central cellular energy sensor, plays a critical role in maintaining metabolic homeostasis by coordinating pathways involved in substrate utilization, mitochondrial function, autophagy, and stress adaptation. Experimental evidence supports a cardioprotective role of AMPK activation, including improved energetic efficiency, attenuation of pathological remodeling, and enhanced cellular resilience. However, emerging data indicate that AMPK signaling is highly context-dependent, with its effects varying according to HF phenotype, disease stage, and isoform-specific activity. While indirect AMPK modulation through established therapies such as metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors has demonstrated clinical benefit, the specific contribution of AMPK to these effects remains incompletely defined. Furthermore, direct pharmacological activation is limited by challenges including tissue specificity, off-target effects, and potential adverse outcomes associated with sustained activation. This review provides a comprehensive overview of AMPK signaling in HF, focusing on its role in metabolic remodeling, mitochondrial regulation, and interaction with key cardioprotective pathways. We also examine current clinical and translational evidence and discuss emerging strategies aimed at achieving isoform-selective and tissue-specific modulation. Collectively, these insights support a shift from broad AMPK activation toward precision-based therapeutic approaches tailored to the disease context.
    Keywords:  AMPK; HFpEF; HFrEF; SGLT2 inhibitors; autophagy; heart failure; metabolism; metformin; mitochondrial dysfunction; precision medicine
    DOI:  https://doi.org/10.3390/biomedicines14061362
  2. Biomolecules. 2026 Jun 15. pii: 873. [Epub ahead of print]16(6):
    SGLT2 Inhibitors in Hypertrophic Cardiomyopathy: Emerging Evidence and Putative Mechanisms.
    Khrystyna Ryabenko, Valérie Schini-Kerth, Patrick Ohlmann, Elena Galli.
      Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disorder and a major cause of heart failure (HF) and sudden cardiac death. Although sarcomeric gene mutations initiate the disease, increasing evidence identifies oxidative stress, mitochondrial dysfunction, and maladaptive nutrient signaling as key drivers of disease progression. Enhanced reactive oxygen species (ROS) production in HCM promotes energetic impairment, calcium mishandling, fibrosis, and the activation of pro-hypertrophic pathways, while disrupting protein quality control and endothelial function. Despite recent therapeutic advances, effective disease-modifying strategies targeting these molecular mechanisms remain limited. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), originally developed for type 2 diabetes, have demonstrated robust cardioprotective effects in HF independent of glycemic control. Beyond their renal actions, SGLT2i modulate myocardial metabolism, reduce oxidative stress, improve mitochondrial function, restore sodium and calcium homeostasis, and attenuate inflammation and maladaptive mTOR activation. Emerging preclinical and translational data suggest that these pleiotropic mechanisms may counteract key pathophysiological processes underlying HCM. This review summarizes the molecular interplay between oxidative stress and hypertrophic remodeling in HCM and explores the rationale for SGLT2 inhibition as a potential disease-modifying therapeutic strategy.
    Keywords:  gliflozines; hypertrophic cardiomyopathy; inflammation; reactive oxygen species; sodium–glucose cotransporter 2 inhibitors
    DOI:  https://doi.org/10.3390/biom16060873
  3. Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00655-8. [Epub ahead of print]45(7): 117577
    Stiffness-induced impairment of GLUT4 trafficking in adult cardiomyocytes.
    Alexia Vite, Tony Guo, Nesrine Bouhrira, Deborah M Eaton, Kenneth C Bedi, Claire F Brady, Jonathan J Edwards, Bea Duric, Keita Uchida, Cassidy Olsen, Lola Dong, Benjamin L Prosser, Zoltan Arany, Kenneth B Margulies.
      Abnormal myocardial fuel utilization contributes to heart failure (HF). Myocardial glucose uptake in response to insulin is suppressed in patients with HF, but the mechanisms of this metabolic inflexibility are not fully understood. The present studies employ culture surfaces with tunable stiffness, quantitatively mimicking the healthy and diseased heart milieu. We observe that human and rat adult cardiomyocytes cultured on stiff surfaces develop blunted insulin-mediated glucose uptake, associated with intracellular aggregation of the high-affinity glucose transporter GLUT4 within the microtubule network, and with impaired contractility. These effects are prevented by blocking stiffness-induced detyrosination of α-tubulin, and can be partially rescued by metformin, through AMPK activation. Similarly, disabling motor proteins that mediate microtubule-based trafficking of GLUT4 independently alter insulin-mediated glucose uptake and contractility in myocytes. These findings demonstrate a cell-autonomous mechanism of stiffness-induced impairment of GLUT4 trafficking and glucose uptake in adult rat and human cardiomyocytes.
    Keywords:  AMPK; CP: cell biology; CP: metabolism; GLUT4; cardiac metabolism; cardiomyocytes; glucose uptakem; heart failure; insulin resistance; mechanical stress; microtubules; α-Tubulin detyrosination
    DOI:  https://doi.org/10.1016/j.celrep.2026.117577
  4. bioRxiv. 2026 Jun 10. pii: 2026.06.06.727699. [Epub ahead of print]
    Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.
    Kyoungmin Kim, Tanvi Shankar, Yaqi Gao, Ian K Williamson, Nathaniel Snyder, Evan P Kransdorf, Ralph DeBerardinis, Heinrich Taegtmeyer, Brandon Faubert, Anja Karlstaedt.
       Background: Cardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. Metabolic dysregulation of cancer cells extends beyond the tumor microenvironment and increases the risk for cardiovascular diseases. One common somatic mutation in cancer cells affects isocitrate dehydrogenase (IDH) 1 and 2, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the cytosol and mitochondria, respectively. IDH1 and 2 mutations cause the production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which allosterically inhibits α-ketoglutarate dehydrogenase (α-KGDH) and is associated with reduced cardiac contractile function.
    Methods: We combined stable isotope tracer studies with computational modeling to investigate the fundamental role of IDH isoforms in cardiac adaptation under oncometabolic stress.
    Results: We uncovered an unexpected cardiac phenotype that expands the role of IDH1 in the heart beyond oxidative metabolism. We quantified the stable isotopomer distributions from glucose and glutamine in perfused working rat hearts and isolated adult ventricular cardiomyocytes using mass spectrometry-based metabolomics. Our analysis revealed that defective mitochondrial metabolism causes the redirection of carbon flux from oxidative towards reductive pathways. Reductive carboxylation of α-KGDH increases glutamine uptake and glutamine-derived citrate formation in working rat heart perfusions and cultured adult mouse ventricular cardiomyocytes. To identify which IDH isoform is responsible for redirecting carbon flux, we developed knockout models of IDH1, IDH2, and IDH3 in adult mouse ventricular cardiomyocytes. Loss of IDH1 expression impaired the reductive formation of citrate and caused functional defects in cardiomyocytes. Lastly, epigenetic analyses of histone marks revealed that IDH1 induces widespread alterations in histone acetylation and tri-methylation.
    Conclusion: Our results highlight a novel role for IDH1 in cardiac metabolism and transcriptional control of metabolic adaptation to tumor-mediated stress and provide evidence that reductive-citrate formation may induce epigenetic modifications in the heart.
    DOI:  https://doi.org/10.64898/2026.06.06.727699
  5. Naunyn Schmiedebergs Arch Pharmacol. 2026 Jun 25.
    Protein phosphatase 2A impairs cardiac uptake of glucose in the mammalian heart.
    Katarina Hadova, Daniel Gündel, Torsten Knieß, Peter Brust, Jan Klimas, Joachim Neumann, Ulrich Gergs.
      Protein phosphatase 2A (PP2A) accounts for approximately half of all serine/threonine phosphatase activity in the mammalian heart. We hypothesised that PP2A, through dephosphorylation of key regulatory enzymes, modulates cardiac glucose uptake and metabolism in vivo. Using positron emission tomography (PET), we studied the uptake of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) in living mice with cardiac-specific overexpression of the catalytic subunit of PP2A (PP2A-TG) as well as in littermate controls (wild-type, WT). Additionally, we analysed the expression of enzymes and transcription factors involved in cardiac glucose metabolism. Cardiac glucose consumption was reduced by 41% (P < 0.05) in PP2A-TG mice relative to WT. Real-time quantitative polymerase chain reaction analysis revealed decreased gene expression of glycogen synthase 1 (- 26%, P < 0.05), glycogen phosphorylase (- 17%, P < 0.05), Mtor (-22%, P < 0.05), peroxisome proliferator-activated receptor gamma (Pparg), and its coactivator PGC-1α (-41% and - 28% respectively; both P < 0.05) in PP2A-TG hearts. Western blotting demonstrated increased protein expression of phosphoinositide 3-kinase (PI3K, 26%, P < 0.05), reduced expression of glycogen synthase (-34%, P < 0.05) and glycogen phosphorylase (-18%, P < 0.05), and enhanced phosphorylation of AKT (95%, P < 0.05) and glycogen synthase kinase-3β (GSK3β, 22%, P < 0.05) in PP2A-TG hearts. These findings indicate that PP2A impairs cardiac glucose metabolism in vivo through modulation of multiple components of glucose handling, including the PI3K/AKT signalling axis, glycogen metabolism, and PPARγ-dependent transcriptional regulation. The effects of PP2A appear to be predominantly indirect. Elevated PP2A expression may therefore be detrimental in heart failure by compromising myocardial energy production.
    Keywords:  2-[18F]fluoro- 2-deoxy-D-glucose ([18F]FDG); Glucose metabolism; Heart; Protein phosphatase 2A; Transgenic mice
    DOI:  https://doi.org/10.1007/s00210-026-05617-x
  6. Nutrients. 2026 Jun 09. pii: 1857. [Epub ahead of print]18(12):
    Determinants of Adherence to a Ketogenic Diet in Patients with Heart Failure with Reduced Ejection Fraction.
    Lee Patricia Liao, Barbara Murphy, Gary C H Gan, Liza Thomas, Luigi Fontana, Shannon McKinn, Sarah Zaman.
      Background: Dietary interventions in heart failure (HF) remain limited, with current guidance focused largely on sodium restriction. Ketone metabolism has emerged as a potential therapeutic target in HF, with ketone supplementation shown to improve cardiac function. However, there are currently no studies investigating factors affecting adherence to a ketogenic diet (KD) in HF. Aim: To explore the factors influencing adherence to a KD in patients with HF to inform future dietary interventions. Method: This qualitative study was embedded within the KETO-HF pilot randomised controlled trial, in which participants with HF with reduced ejection fraction undertook a 4-month KD. Consenting participants were invited to complete semi-structured interviews. Interviews were audio-recorded, deidentified and transcribed verbatim. Data were analysed using thematic analysis with a mixed inductive-deductive strategy. Results: Fifteen participants were interviewed. Facilitators of adherence were: (1) personal motivation and self-regulation; (2) improved well-being; (3) interpersonal support and; (4) adaptive strategies and improved nutritional literacy. Barriers included: (1) early-phase physiological and psychological challenges; (2) social and cultural friction; (3) competing family and work demands and; (4) limited availability of suitable foods, particularly difficulty managing social situations and dining out. Conclusions: Adherence to a KD in people with HF is shaped by a combination of individual and social factors. These findings highlight the need for improved education, support, and increased food options to optimise implementation of dietary ketosis in HF.
    Keywords:  adherence; barriers; dietary patterns; facilitators; heart failure; ketogenic diet; qualitative
    DOI:  https://doi.org/10.3390/nu18121857
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒30 at 15:13.