bims-hafaim 2026-08-16 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2026–08–16
seven papers selected by
Kyle McCommis, Saint Louis University

Diet-Associated Regulation of Cardiac Metabolism: Molecular Determinants and Pathophysiological Consequences.
Research progress on metabolic abnormalities in myocardial hypertrophy.
Murine metabolic HFpEF is associated with altered mitochondrial substrate handling and S-nitrosylation remodeling.
Loss of the cardiac-enriched mitochondrial transporter SLC25A34 promotes heart failure by attenuating fatty acid oxidation.
Metabolism of fructose in the heart favors glycerate production and is linked to cardiac dysfunction in diabetes.
Dual inhibition of SGLT 1 and 2 by sotagliflozin alleviates intracellular sodium overload and improves cardiometabolic remodelling in uraemic cardiomyopathy.
Natural ERRα Activator Formononetin Ameliorates Anthracycline Cardiotoxicity via Metabolic Improvement.

Nutrients. 2026 Jul 27. pii: 2451. [Epub ahead of print]18(15):

Diet-Associated Regulation of Cardiac Metabolism: Molecular Determinants and Pathophysiological Consequences.

Gaetano Pacinella, Anna Maria Ciaccio, Carlo Domenico Maida, Vittoriano Della Corte, Giuseppe Miceli, Mario Daidone, Cosimo Quaranta, John Sebastian Soldano, Antonino Tuttolomondo.

  The heart is a highly energy-demanding organ that depends on metabolic flexibility to adjust substrate utilization in response to changes in nutrient availability, endocrine signals, and energetic demands. Accumulating evidence demonstrates that dietary patterns are key determinants of myocardial metabolic homeostasis, affecting substrate selection, mitochondrial function, nutrient-sensing pathways, and long-term transcriptional and epigenetic regulation. This review analyzes the molecular mechanisms through which diet regulates cardiac metabolism and explores how chronic nutritional exposures influence the myocardial energetic phenotype. The physiological regulation of cardiac substrate utilization is described, with emphasis on fatty acids, glucose, ketone bodies, and branched-chain amino acids, underscoring the importance of metabolic flexibility in sustaining cardiac efficiency. The regulation of substrate transport and oxidation is examined, including the roles of the carnitine shuttle, insulin signaling, AMPK, mTOR, PPARα-PGC-1α, SIRT3, and other nutrient-sensing networks that coordinate mitochondrial ATP production. The effects of dietary composition and meal timing, such as caloric restriction and intermittent fasting, are discussed as modulators of myocardial metabolism. The adverse effects of chronic nutrient excess are reviewed, including lipotoxicity, glucotoxicity, insulin resistance, mitochondrial dysfunction, oxidative stress, pseudo-hypoxia, fetal metabolic reprogramming, and maladaptive cardiac remodeling. Recent findings on the gut-heart axis, microbiota-derived metabolites, circadian regulation, and metabolic-epigenetic interactions are also considered. Overall, current evidence supports the view that diet is an important and potentially modifiable regulator of the cardiac metabolic phenotype. Advancing the understanding of diet-metabolism interactions may enable the development of targeted nutritional strategies to maintain metabolic flexibility, enhance cardiac bioenergetics, and prevent the progression of heart failure and other cardiometabolic diseases.

Keywords:  cardiac metabolism; cardiac remodelling; diet; glucotoxicity; gut–heart axis; heart failure; lipotoxicity; metabolic flexibility; mitochondrial dysfunction; myocardial energetics; nutrient sensing; precision nutrition

DOI:  https://doi.org/10.3390/nu18152451
Front Cardiovasc Med. 2026 ;13 1912835

Research progress on metabolic abnormalities in myocardial hypertrophy.

Xueru Liu, Yanlin Liu, Meng Huang, Fan Ouyang, Yukun Li.

  Myocardial hypertrophy is initially an adaptive response to mechanical, neurohumoral, or metabolic stress, but persistent hypertrophy increases the risk of heart failure, arrhythmia, and death. Metabolic remodeling is now recognized as an early driver rather than a passive consequence of increased workload. This review aims to summarize recent advances in metabolic abnormalities in myocardial hypertrophy, focusing on pathophysiological mechanisms, biomarker implications, therapeutic opportunities, and future directions. Current evidence establishes that hypertrophic myocardium exhibits substrate inflexibility, impaired fatty acid oxidation, increased glycolysis with anaplerotic rerouting, mitochondrial calcium and quality-control defects, NAD+-sirtuin disruption, redox stress and ferroptosis, branched-chain amino acid accumulation, and ketone body adaptation. These abnormalities interact with canonical growth pathways including AMPK, mTOR, PKA, YAP, STAT3, ERR, SIRT3/SIRT5/SIRT6, and inflammatory programs. In biomarker research, metabolomics has moved from single metabolites toward integrated panels combining circulating acylcarnitines, amino acids, ketones, redox markers, and imaging-derived hypertrophy; however, interpretation remains strongly context-dependent on etiology, disease stage, sex, renal function, diabetes, and therapy. Therapeutically, phenotype-specific strategies-such as NAD+ repletion, SIRT activation, BCAA catabolism modulation, and ferroptosis inhibition-are emerging but require biomarker-guided trials. Despite these advances, critical challenges remain: distinguishing adaptive compensation from maladaptive remodeling, validating tissue-to-plasma concordance, establishing longitudinal human cohorts with serial metabolomics, and developing harmonized multi-omics pipelines. By addressing these core issues, this review provides a comprehensive, clinically oriented perspective on the current state and future trajectory of metabolic research in myocardial hypertrophy, emphasizing the need for biomarker-enriched interventions before irreversible remodeling occurs.

Keywords:  biomarkers; branched-chain amino acids; cardiac metabolism; fatty acid oxidation; glycolysis; ketone bodies; metabolic remodeling; metabolomics

DOI:  https://doi.org/10.3389/fcvm.2026.1912835
Redox Biol. 2026 Aug 12. pii: S2213-2317(26)00348-4. [Epub ahead of print]96 104349

Murine metabolic HFpEF is associated with altered mitochondrial substrate handling and S-nitrosylation remodeling.

Huihui Li, Hanyu Cui, Daiyu Wang, Florian Leuschner, Joerg Heineke, Jiong Hu, Sofia-Iris Bibli.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition with incompletely defined myocardial mechanisms. Here, using a two-hit murine model of cardiometabolic HFpEF induced by high-fat diet and endothelial nitric oxide synthase inhibition, we define a mitochondrial metabolic phenotype characterized by altered substrate handling, redox stress, and S-nitrosylation remodeling. While global proteomic changes were modest, metabolomic profiling revealed selective remodeling of tricarboxylic acid cycle intermediates, increased dicarboxylic acids, and altered redox-associated metabolites, consistent with mitochondrial metabolic and redox imbalance in this experimental setting. S-nitrosylation proteomics demonstrated a highly organized and bidirectional remodeling pattern affecting proteins involved in fatty acid/lipid metabolism, carbohydrate metabolism, mitochondrial energy metabolism, amino acid and organic acid metabolism, nucleotide/co-factor metabolism, and redox defense. Stable isotope tracing showed reduced glucose-derived and increased palmitate-derived acetyl-CoA in HFpEF, whereas Na-βHB reduced palmitate contribution and increased βHB-derived acetyl-CoA without restoring glucose contribution, indicating substrate redistribution and preserved ketone oxidation. Na-βHB supplementation increased oligomycin-sensitive respiration in freshly prepared left ventricular tissue, partially normalized selected TCA-cycle intermediates, reduced mitochondrial ROS and the NADH/NAD+ ratio, restored the GSH/GSSG ratio, and improved diastolic function without altering ejection fraction. Together, these findings define a redox-sensitive mitochondrial metabolic state in the HFD/l-NAME model and identify ketone supplementation as a partial metabolic rescue strategy in this context. At the same time, these findings highlight an important limitation of the murine HFD/l-NAME model, which should be interpreted as an experimental system for studying high-fat-induced cardiometabolic stress rather than as a metabolic equivalent of human HFpEF.

DOI: https://doi.org/10.1016/j.redox.2026.104349
J Mol Cell Biol. 2026 Aug 10. pii: mjag026. [Epub ahead of print]

Loss of the cardiac-enriched mitochondrial transporter SLC25A34 promotes heart failure by attenuating fatty acid oxidation.

Jieyuan Xue, Yin Long, Jiayu Zhou, Yuxuan Chen, Yuanji Huang, Shengyan Pu, Mengyu Huang, Chenfeng Wang, Junxi Qian, Xumin Hou, Liang Fang, Ben He, Xu-Yun Zhao.

  Heart failure is characterized by profound structural and metabolic remodeling. Members of the solute carrier family 25 (SLC25), as inner mitochondrial membrane proteins, play critical roles in mitochondrial dysfunction during heart failure; however, the role of cardiac-enriched SLC25 family members remains incompletely understood. In this study, we identify solute carrier family 25 member 34 (SLC25A34) as a previously unrecognized mitochondrial regulator of cardiac energy metabolism in heart failure. SLC25A34 is highly enriched in the heart and predominantly expressed in adult cardiomyocytes. Its expression progressively increases during postnatal cardiac development, is closely associated with fatty acid-based energy utilization, and is inducible by palmitate. In contrast, SLC25A34 expression is markedly reduced in failing human hearts and multiple mouse models of heart failure. Mechanistically, oxidative stress during heart failure suppresses SLC25A34 expression in cardiomyocytes. Genetic deletion of Slc25a34 exacerbates cardiac dysfunction and adverse remodeling following transverse aortic constriction, without significantly affecting cardiac hypertrophy. Integrated biochemical, transcriptomic, and functional analyses demonstrate that loss of SLC25A34 suppresses the AMPK-CPT1B axis, thereby impairing fatty acid oxidation, leading to reduced ATP production, lipid droplet accumulation, and disrupted redox homeostasis. Conversely, adeno-associated virus-mediated cardiac-specific overexpression of Slc25a34 significantly mitigates heart failure progression. Collectively, these findings establish SLC25A34 as a key mitochondrial regulator linking fatty acid metabolism, energy sensing, and redox homeostasis and suggest that targeting SLC25A34 may represent a novel therapeutic strategy for heart failure.

Keywords:  SLC25A34; cardiomyocyte; fatty acid oxidation; heart failure; redox homeostasis

DOI:  https://doi.org/10.1093/jmcb/mjag026
J Mol Cell Cardiol. 2026 Aug 13. pii: S0022-2828(26)00121-5. [Epub ahead of print]218 121-129

Metabolism of fructose in the heart favors glycerate production and is linked to cardiac dysfunction in diabetes.

Marco Annandale, Dominic Lachance, Isabelle F Robillard, George Guo, Xun Li, Parisa Koutsifeli, Lorna J Daniels, Erica Zarate, Angus C Grey, Lea M D Delbridge, Matthieu Ruiz, Christine Des Rosiers, Kimberley M Mellor.

  Increased cardiac risk in diabetes has been linked to disturbances in myocardial metabolism. Circulating and cardiac fructose levels are elevated in diabetes but the relationship between fructose and cardiac pathology is unclear. The goal of this study was to assess myocardial capacity for fructose metabolism and evaluate the time-course of cardiac fructose accumulation relative to the emergence of cardiac functional impairment in diabetic rats. Cardiac capability for fructose metabolism to support function was demonstrated in ex vivo working mouse hearts perfused with 11 mM fructose. Using isotope-labeled fructose [U13C], we observed 13C enrichment into downstream metabolites glyceraldehyde, glycerate, pyruvate, lactate, and mitochondrial acetyl-CoA in perfused working mouse hearts. Metabolite profiling demonstrated that relative to glucose, myocardial fructose metabolism favored glycerate production. In diabetic rats (streptozotocin, 55 mg/kg), cardiac fructose elevation was evident prior to the onset of cardiac dysfunction. This study provides proof-of-principle evidence that fructose metabolism is operational in the working heart and identifies key fructose-derived metabolites. The finding that cardiac fructose elevation precedes functional impairment supports the contention that fructose may be an early instigator of diabetic cardiomyopathy and further investigation is now warranted. NEW AND NOTEWORTHY (<75 WORDS): Circulating and cardiac fructose levels are elevated in diabetes but the relationship between fructose and cardiac pathology is unclear. This study provides proof-of-principle evidence that fructose metabolism is operational in the working heart and identifies that cardiac fructose metabolism favors production of glycerate. In diabetes, cardiac fructose elevation precedes functional impairment supporting the contention that fructose may be an early instigator of diabetic cardiomyopathy.

Keywords:  Cardiac metabolism; Diabetic cardiomyopathy; Isotope tracing; Metabolomics

DOI:  https://doi.org/10.1016/j.yjmcc.2026.08.003
Cardiovasc Res. 2026 Aug 11. pii: cvag167. [Epub ahead of print]

Dual inhibition of SGLT 1 and 2 by sotagliflozin alleviates intracellular sodium overload and improves cardiometabolic remodelling in uraemic cardiomyopathy.

Megan Young, Anja Karlstaedt, Sanushi Dambure, Jack J J J Miller, Tong Guo, Xin Zhou, Zenouska Ramchunder, Jair Gonzalez Marques Junior, Muriel Nobles, Andrew Tinker, Kyuongmin Kim, Amanda R Purcell, Sarah J Glastras, Fenn Cullen, Thomas R Eykyn, Alex Von Kriegsheim, Blanca Rodriguez, Michelangelo Campanella, Michael J Shattock, Nay Aung, Claudia P Cabrera, Magdi M Yaqoob, Dunja Aksentijevic.

AIMS: Chronic kidney disease (CKD) is associated with uraemic cardiomyopathy characterised by early metabolic dysfunction. Elevated myocardial intracellular sodium (Naᵢ) has emerged as a driver of cardiometabolic remodelling, however, its role in CKD and therapeutic modulation remains unclear. We investigated whether dual sodium-glucose cotransporter (SGLT)1/2 inhibition with sotagliflozin (SOTA) targets Naᵢ and improves cardiac metabolism in CKD.
METHODS AND RESULTS: CKD was induced in male Wistar rats by 5/6 nephrectomy and assessed after 4 weeks. Cardiac phenotype was evaluated using in vivo echocardiography and ex vivo Langendorff perfusion combined with 23Na and 31P NMR spectroscopy. CKD hearts exhibited preserved systolic but impaired diastolic function and a marked elevation in myocardial Naᵢ, identifying Naᵢ overload as an early feature of uraemic cardiomyopathy. Cardiac metabolomic profiling and flux modelling demonstrated widespread suppression of central carbon metabolism, redox imbalance despite preserved PCr/ATP. In silico electrophysiological simulations predicted Naᵢ-driven Ca2+ dysregulation consistent with in vivo diastolic dysfunction. Chronic SOTA treatment (3 weeks, in vivo) normalised myocardial Naᵢ and partially reversed metabolic remodelling. Acute SOTA exposure (20-minute, Langendorff-perfusion) similarly reduced Naᵢ in CKD hearts but not in controls, indicating a direct, disease-selective myocardial effect. Naᵢ normalisation was accompanied by improved redox state and restoration of mitochondrial metabolic flux, without changes in expression of canonical Na + -handling proteins.
CONCLUSION: Myocardial Naᵢ overload emerges as an early and potentially modifiable feature of uraemic cardiomyopathy. Dual SGLT1/2 inhibition with SOTA directly lowers Naᵢ and improves cardiac metabolic homeostasis, supporting Naᵢ as a mechanistically relevant and potentially targetable pathway in CKD-related cardiac remodelling.

DOI: https://doi.org/10.1093/cvr/cvag167
Circ Res. 2026 Aug 12.

Natural ERRα Activator Formononetin Ameliorates Anthracycline Cardiotoxicity via Metabolic Improvement.

Xiaoping Wang, Guanjing Ling, Yan Wei, Weili Li, Yi Zhang, Ziyi Yin, Kai Wei, Qian Chen, Lei Dong, Yun Chen, Wei Wang, Qi Qiu, Yong Wang.

   BACKGROUND: Anthracycline-induced cardiotoxicity (AIC) limits life-saving chemotherapy and is driven by early metabolic remodeling. The nuclear receptor ERRα (estrogen-related receptor α) is a master regulator of cardiac energy metabolism, but the temporal dynamics of its downregulation, its causal role in AIC pathogenesis, and whether it can be pharmacologically activated to confer protection remain undefined.
METHODS: We performed temporal protein analysis in a porcine AIC model. Using cardiomyocyte-specificgain- and loss-of-function mouse models, we assessed the causal role of ERRα. Mechanistic studies included ChIP-qPCR, reporter assays, and microscale thermophoresis to investigate the natural compound formononetin. Human breast cancer patient-derived organoids were used to evaluate anticancer activity.
RESULTS: ERRα expression was selectively downregulated in AIC pig hearts and cardiac tissue from chemotherapy-treated patients. Temporal analysis in pigs revealed that ERRα reduction occurred at the subclinical (6-week) stage, preceding overt cardiac dysfunction. Cardiomyocyte-specific ERRα overexpression activated mitochondrial gene programs, enhanced fatty acid oxidation, and preserved systolic function after doxorubicin challenge, whereas ERRα knockdown exacerbated bioenergetic failure and cardiac dysfunction. Through drug screening, we identified formononetin as a potent and selective ERRα agonist. Formononetin enhanced ERRα transcriptional activity, improved mitochondrial metabolism, and protected against AIC in both murine and porcine models. Mechanistically, ChIP-qPCR demonstrated increased ERRα occupancy at target gene promoters, and microscale thermophoresis confirmed direct binding of formononetin to the ERRα/PGC-1α complex, indicating allosteric stabilization. Finally, in human breast cancer patient-derived organoids, formononetin alone reduced viability and proliferation, and combined with doxorubicin further enhanced antitumor efficacy.
CONCLUSIONS: ERRα downregulation is a causal early event in the pathogenesis of AIC. Formononetin acts as a first-in-class selective ERRα activator that improves cardiac metabolism and function while retaining anticancer activity, supporting its potential as a dual-action cardioprotective agent during anthracycline therapy.

Keywords:  anthracycline; cardiotoxicity; fatty acid; formononetin; organoids

DOI:  https://doi.org/10.1161/CIRCRESAHA.126.329042