bims-hafaim 2026-01-18 papers

Issue of 2026–01–18
six papers selected by
Kyle McCommis, Saint Louis University

Circ Res. 2026 Jan 16. 138(2): e327929

Fatty Acid Transport at the Heart of Metabolic Adaptation.

Keywords: Editorials; heart failure; lipid metabolism; metabolism

DOI: https://doi.org/10.1161/CIRCRESAHA.125.327929

Eur Heart J. 2026 Jan 13. pii: ehaf1060. [Epub ahead of print]

Anthracycline cardiotoxicity: role of metabolic vulnerability induced by cardiac pressure overload.

Carlos Galán-Arriola, Daniel Pérez-Camargo, Inmaculada Jorge, Víctor Bautista, Ali Ayaon-Albarrán, Claudia Pérez-Martínez, Antonio de Molina-Iracheta, Laura Cádiz, Danielle Medina-Hernández, Carlos Caballero-Henares, Gonzalo J Lopez-Martín, Jesús Vázquez, Julien Ochala, Valentin Fuster, Javier Sánchez-González, Borja Ibáñez.

BACKGROUND AND AIMS: Hypertension and valvular heart disease, both associated with left ventricular (LV) pressure overload, increase the risk of anthracycline cardiotoxicity. While epidemiologically established, the underlying mechanisms remain unclear, precluding identification of therapeutic targets.
METHODS: Two-month-old Yucatan pigs (males and females) underwent aortic banding to induce LV pressure overload or no operation. After 4 months, animals received a low-risk cumulative dose of doxorubicin (5 weekly 1 mg/kg intravenous injections) or vehicle, generating four groups: (i) healthy controls (no LV overload, no doxorubicin), (ii) Dox (doxorubicin, no LV overload), (iii) Banding (B: LV overload, no doxorubicin), and (iv) B + Dox (LV overload plus doxorubicin). Cardiac function, structure, and metabolism were assessed over 8 months by cardiac magnetic resonance, magnetic resonance spectroscopy, and hybrid positron emission tomography/computed tomography. At study end, proteomics and mitochondrial structure and function were analysed. Complementary in vivo and ex vivo studies examined the mechanistic role of energetic imbalance.
RESULTS: LV overload increased LV mass (P < .0001) and ejection fraction (P = .0081), with compensatory metabolic changes (drop in phosphocreatine (P = .022)). Low-risk Dox alone altered myocardial metabolism (increased glucose uptake, P = .014) but preserved cardiac function. In pigs with pre-existing LV pressure overload, doxorubicin increased mortality (P < .0001 vs all other groups), reduced left ventricular ejection fraction (LVEF) (P < .0001), increased fibrosis, and impaired mitochondrial respiration (P = .032). In HL-1 cardiomyocytes, reducing energy demand with mavacamten rescued cell viability under combined doxorubicin and hypertrophic stress.
CONCLUSIONS: LV pressure overload increases myocardial susceptibility to anthracycline cardiotoxicity by inducing a high-energy-demand state. Anthracycline treatment, even at a low-risk dose, disrupts compensatory mechanisms in the pressure-overloaded heart, rapidly leading to cardiac dysfunction and heart failure. Preventive strategies targeting this metabolic vulnerability are urgently needed for patients with extant LV pressure overload (e.g. hypertension or valvular heart disease) who are undergoing anthracycline therapy.

Keywords: Anthracyclines; Cardiooncology; Heart failure; MR spectroscopy

DOI: https://doi.org/10.1093/eurheartj/ehaf1060

bioRxiv. 2026 Jan 06. pii: 2026.01.05.697798. [Epub ahead of print]

The Epigenetic Regulator Histone Demethylase KDM5A is Activated and Pathogenic in a Mouse Model of Heart Failure.

Manisha Deogharia, Chitra Lekha Reddy, Ritapa Chaudhuri, Manogna Sai Chirasani, Abhinav K Jain, Leila Rouhi, A J Marian, Priyatansh Gurha.

Heart failure is a complex disease characterized by the dysregulation of gene expression that culminates in cardiac dysfunction. Epigenetic regulators play a critical role in control of transcription and are increasingly implicated in the pathogenesis of heart failure. We recently showed that the histone demethylase KDM5A is reactivated in the heart of human patients and mouse models of heart failure. However, its pathogenic role in heart failure remained unknown. Utilizing a mouse model of heart failure caused by the deletion of the Lmna gene in cardiomyocytes and referred to as LMNA-cardiomyopathy (LMNA-CMP), we show that KDM5A is activated, and expression levels of genes involved in myocyte structure and function, including oxidative phosphorylation (OXPHOS), are suppressed. To determine the pathogenic role of KDM5A in heart failure, the Kdm5a gene was specifically deleted in cardiomyocytes in LMNA-CMP mice ( Myh6-Cre:Lmna F/F : Kdm5a F/F ). The deletion of the Kdm5a gene improved cardiac function, prolonged survival, attenuated fibrosis, and reduced cell death in LMNA-CMP mice. Transcriptome analysis showed that the deletion of the Kdm5a gene restored the expression of over 1,400 dysregulated genes, including those involved in fatty acid metabolism, myogenesis, and OXPHOS in the Myh6-Cre:Lmna F/F : Kdm5a F/F mice. Genome-wide profiling of the epigenetic histone mark H3 lysine 4 trimethylation (H3K4me3), the main target of KDM5A, by CUT&RUN assay showed that deletion of the Kdm5a gene partially restored H3K4me3 deposits at loci encoding cardiac transcription factors and metabolic regulators, including Tbx5 and Esrrg , with concomitant rescue of their downstream targets. These findings identify KDM5A as a key epigenetic regulator of cardiomyocyte gene expression and uncover a mechanistic role for KDM5A in the pathogenesis of heart failure.

DOI: https://doi.org/10.64898/2026.01.05.697798

J Food Drug Anal. 2025 Dec 15. 33(4): 421-433

Selective sodium-glucose cotransporter two inhibitor empagliflozin ameliorates diabetic cardiomyopathy by activating the AMPK/TFEB signaling pathway.

Man-Chen Hsu, Ru-Wen Chang, Mu-Chun Wang, Chia-Hui Chen, Wen-Hua Chen, Tzong-Shyuan Lee, Chih-Hsien Wang.

The highly selective SGLT2 inhibitor (SGLT2i) is reported to have beneficial effects on diabetic cardiac hypertrophy; however, the molecular mechanisms underlying the cardioprotection of SGLT2i are not fully understood. In this study, we investigated the impact of the SGLT2 Inhibitor empagliflozin (EMPA) on diabetic hearts and its regulatory mechanisms in high-fat-diet (HFD)- and streptozotocin (STZ)-treated rats. Male rats orally administered HFD/STZ treatment for eight weeks, with or without EMPA (10 mg/kg), were used as our in vivo model. Hematoxylin and eosin (H&E) staining was used for histological examination. Western blot analysis and immunohistochemistry were used to analyze the expression of proteins. Daily EMPA administration prevented the HFD/STZ treatment-induced cardiac hypertrophy by activating the AMP-activated protein kinase (AMPK)/transcription factor EB (TFEB)-mediated upregulation of autophagy- and antioxidant-related proteins. Moreover, EMPA treatment decreased oxidative stress by increasing the antioxidant capacity and protein expression of antioxidant proteins while downregulating the levels of 4-hydroxy-2E-nonenal in the hearts of diabetic rats. Furthermore, EMPA treatment decreased cardiomyocyte apoptosis and increased heart mitochondrial function. The AMPK/TFEB signaling-mediated increase in autophagy, antioxidant capacity, mitochondrial function, and attenuated cardiomyocyte apoptosis may be crucial in the anti-hypertrophic effect conferred by SGLT2i. Our clinical implications suggest a novel pharmacological approach for treating diabetic cardiomyopathy by modulating autophagy and redox homeostasis.

DOI: https://doi.org/10.38212/2224-6614.3563

J Inherit Metab Dis. 2026 Jan;49(1): e70142

Energy Metabolism Under Stress: Late-Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in Ndufs4 KO Mice.

Karin Terburgh, Nastassja Sweeney, Roan Louw.

The deficiency of mitochondrial complex I (CI), a key regulator of cellular energy homeostasis and metabolic flexibility, is a prevalent driver of cardiovascular pathology in mitochondrial disorders. The Ndufs4 knockout (KO) mouse model of Leigh syndrome (LS), which lacks a critical CI subunit, exhibits severe cardiac abnormalities secondary to encephalomyopathy. However, the metabolic basis of LS-associated cardiac dysfunction remains poorly understood. This study aims to evaluate how whole-body CI deficiency affects cardiac bioenergetics and metabolism in late-stage Ndufs4 KO mice. We assessed respiratory chain enzyme activities and oxygen consumption rates using kinetic spectrophotometric assays and high-resolution respirometry, respectively, in mitochondria isolated from Ndufs4 KO and wild-type mouse hearts. Cardiometabolic profiling was performed on a well-powered cohort, employing untargeted GC-TOFMS, 1H-NMR and semi-targeted LC-MS/MS. Ndufs4 KO hearts showed a 98.9% reduction in CI activity and a 63.9% decline in CI-driven respiration, halving CI's contribution to combined CI + II respiration and prompting a shift toward CII-driven respiration. Cardiometabolic profiles revealed significant reductions in energy-generating substrates, including long-chain fatty acids, glucose, lactic acid and 3-hydroxybutyric acid, along with lower levels of anaplerotic amino acids and TCA cycle intermediates, particularly succinic acid. Additionally, profound disruptions were observed in dimethylglycine, glutamic acid and lysine metabolism. We conclude that whole-body CI deficiency results in severe cardiac bioenergetic and metabolic dysregulation, characterised by reduced CI-dependent respiration and extensive substrate reduction across multiple metabolic pathways. These findings underscore the metabolic vulnerability of the CI-deficient heart and suggest potential therapeutic targets for managing cardiomyopathy in mitochondrial disease.

Keywords: Leigh syndrome; Ndufs4 knockout mice; complex I deficiency; heart metabolism

DOI: https://doi.org/10.1002/jimd.70142

Circ Rep. 2026 Jan 09. 8(1): 39-47

Effects of Protein and Amino Acid Supplementation on Physical Performance in Patients With Chronic Heart Failure　- A Systematic Review and Meta-Analysis.

Hirotada Maeda, Yasuyuki Kurasawa, Yuto Fujita, Minoru Wakasa, Takashi Kitagawa.

Background: This study aimed to evaluate the effects of protein and amino acid supplementation on physical performance in patients with chronic heart failure (CHF).
Methods and Results: Studies from PubMed, the Cochrane Library, CINAHL, Web of Science, and PEDro published up to August 2024 were identified using a comprehensive strategy with no limitations on publication date or language. The primary outcome was physical performance, assessed using the 6-min walk distance (6MWD) test. This study included 15 randomized controlled trials involving a total of 744 patients. Control groups received either a placebo or usual care, including standard heart failure treatment. The meta-analysis demonstrated a significant improvement in 6MWD in the supplementation group compared with controls (mean difference 35.25 m; 95% confidence interval 15.93-54.58; I2=38%). Subgroup analysis showed no significant difference between supplementation alone and supplementation combined with exercise, suggesting independent effects. Patients aged ≥65 years showed similar benefits.
Conclusions: Our meta-analysis indicated that physical performance in patients with CHF was improved by using protein and amino acid supplementation, particularly in older adults or those unable to engage in adequate exercise therapy. However, the overall quality of the evidence was very low.

Keywords: Amino acid; Heart failure; Physical performance; Protein

DOI: https://doi.org/10.1253/circrep.CR-25-0100