bims-hafaim 2025-11-16 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–11–16
eight papers selected by
Kyle McCommis, Saint Louis University

PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
β-Hydroxybutyrylation Links Ketone Metabolism to Mitochondrial Remodeling in Diabetic Cardiomyopathy.
Nuclear Receptor Subfamily 4 Group A Member 1 Exacerbates Cardiac Remodeling by Inhibiting Mitochondrial Function Through the Peroxisome Proliferator-Activated Receptor γ Coactivator-1α/Nuclear Respiratory Factor 1/Transcription Factor A Mitochondrial Axis.
Glycometabolic cardiac dysfunction in HFpEF: lessons from multi-omics studies.
Response by Zile et al to Letter Regarding Article, "Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity".
Letter by Zhao et al Regarding Article, "Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity".
SGLT2 inhibitors and left atrial function in heart failure with reduced or mildly reduced ejection fraction.
Intravenous mitochondrial transplantation as an adjunctive therapy for dilated cardiomyopathy.

J Am Heart Assoc. 2025 Nov 11. e043921

PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.

Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Jie Zhu, Anna Faakye, Kenneth M Humphries.

   BACKGROUND: The heart's constant energy demands make metabolic flexibility critical to its function as nutrient availability varies. The enzyme phosphofructokinase-2/fructose 2,6-bisphosphatase (PFKFB2) contributes to this flexibility by acting as a positive or negative regulator of cardiac glycolysis. We have previously shown that PFKFB2 is degraded in the diabetic heart and that a cardiac-specific PFKFB2 knockout (cKO) impacts ancillary glucose pathways and mitochondrial substrate preference. Therefore, defining PFKFB2's role in mitochondrial metabolic flexibility is paramount to understanding both metabolic homeostasis and metabolic syndromes. Further, it is unknown how PFKFB2 loss impacts the heart's response to acute stress. Here, we examined how cardiac mitochondrial flexibility and the posttranslational modification O-GlcNAcylation are affected in cKO mice in response to fasting or pharmacologic stimulation.
METHODS: cKO and litter-matched controls were euthanized in the fed or fasted (12 hours) states, with or without a 20-minute stimulant stress of caffeine and epinephrine. Mitochondrial respiration, metabolomics, and changes to systemic glucose homeostasis were evaluated.
RESULTS: cKO mice had moderate impairment in mitochondrial metabolic flexibility, affecting downstream glucose oxidation, respiration, and carnitine palmitoyl transferase 1 activity. O-GlcNAcylation, a product of ancillary glucose metabolism, was upregulated in cKO hearts in the fed state, but this was ameliorated in the fasted state. Furthermore, metabolic remodeling in response to PFKFB2 loss was sufficient to impact circulating glucose in fasted and stressed states.
CONCLUSIONS: PFKFB2 is essential for fed-to-fasted changes in cardiac metabolism and plays an important regulatory role in protein O-GlcNAcylation. Its loss also affects systemic glucose homeostasis under stressed conditions.

Keywords:  O‐GlcNAc; O‐GlcNAcylation; PFK‐2; glycolysis; metabolic flexibility

DOI:  https://doi.org/10.1161/JAHA.125.043921
Diabetes. 2025 Nov 10. pii: db250496. [Epub ahead of print]

β-Hydroxybutyrylation Links Ketone Metabolism to Mitochondrial Remodeling in Diabetic Cardiomyopathy.

Haoran Jing, Meixin Shi, Ye Wang, Rongyi Cao, Xiaoxue Li, Xin Zhong, Shiyun Dong, Can Wei.

Diabetic cardiomyopathy (DbCM) is characterized by metabolic remodeling and energetic stress independent of coronary artery disease. Increased reliance on fatty acid and ketone body metabolism has been observed in DbCM, but the regulatory mechanisms linking altered substrate use to myocardial dysfunction remain poorly understood. In particular, lysine β-hydroxybutyrate (Kbhb), a ketone body-derived, posttranslational modification, has emerged as a potentially critical regulator but has not been fully investigated. We conducted a comprehensive multiomics study integrating metabolomics, transcriptomics, proteomics, and Kbhb-specific proteomics on myocardial tissues in a well-established mouse model of DbCM. Kbhb-modified proteins were systematically mapped and quantified, followed by motif, subcellular localization, and protein-protein interaction analyses. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Kbhb profiling revealed extensive mitochondrial protein modification, with Atp5f1a-K239 identified as a key modification site strongly correlated with β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb as a potential metabolic-epigenetic modifier linking ketone body availability to the regulation of mitochondrial proteins in DbCM. Our findings provide novel insights into metabolic-epigenetic cross talk and identify potential therapeutic targets for interventions to restore mitochondrial function in alleviating diabetic heart disease.
ARTICLE HIGHLIGHTS: We performed a multiomics study to better understand dysfunctions in diabetic cardiomyopathy (DbCM) and specifically identify links between lysine β-hydroxybutyrylation (Kbhb), a ketone body-derived, posttranslational modification, and cardiac dysfunction. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Mitochondrial proteins showed that high Kbhb modification and modification of the Atp5f1a-K239 site were strongly correlated with high β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb modification of mitochondrial proteins as a potential mechanism linking ketone body availability to mitochondrial function in DbCM.

DOI: https://doi.org/10.2337/db25-0496
J Am Heart Assoc. 2025 Nov 11. e042774

Nuclear Receptor Subfamily 4 Group A Member 1 Exacerbates Cardiac Remodeling by Inhibiting Mitochondrial Function Through the Peroxisome Proliferator-Activated Receptor γ Coactivator-1α/Nuclear Respiratory Factor 1/Transcription Factor A Mitochondrial Axis.

Chun-Yan Kong, Ming-Yu Wang, Yu-Lan Ma, Zhen Guo, Zheng Yang, Qi-Zhu Tang.

   BACKGROUND: Heart failure is characterized by cardiac dysfunction, cardiac remodeling, and mitochondrial dysfunction. NR4a1 (nuclear receptor subfamily 4 group A member 1) plays a crucial role in regulating mitochondrial function and biological performance in various diseases. The main objective of this study was to investigate the influence of NR4a1 on cardiac hypertrophy and uncover its underlying mechanism.
METHODS: A mouse model was established by transverse aortic constriction surgery, and an in vitro model was established by phenylephrine-treated neonatal rat ventricular myocytes. Mice were transfected with adeno-associated virus 9 to assess the role of NR4a1 in cardiac hypertrophy. We used PGC1α (peroxisome proliferator-activated receptor γ coactivator-1α) cardiac-specific knockout mice for subsequent experiments to investigate the impact of NR4a1 on mitochondrial bioenergetics.
RESULTS: NR4a1 overexpression significantly exacerbates transverse aortic constriction-induced cardiac remodeling and cardiac dysfunction, and NR4a1 knockdown attenuates cardiac remodeling and cardiac dysfunction. Mechanistically, NR4a1 modulated cardiac remodeling and heart failure by impairing mitochondrial bioenergetics through PGC1α/NRF1 (nuclear respiratory factor 1)/TFAM (transcription factor A mitochondrial) axis. Inhibition of PGC1α activation is critical for NR4a1 to impair mitochondrial bioenergetics in cardiac hypertrophy. Furthermore, cardiac-specific PGC1α knockdown counteracts heart failure and mitochondrial dysfunction ameliorated by NR4a1 knockdown.
CONCLUSIONS: Collectively, our findings demonstrate that NR4a1 drives pathological cardiac remodeling and heart failure progression by suppressing the PGC1α/NRF1/TFAM axis, leading to impaired mitochondrial function. Targeting NR4a1 and its interactions with PGC1α may hold promise for the development of novel therapeutic strategies for treating cardiac hypertrophy.

Keywords:  NR4a1; PGC1α; cardiac remodeling; energy metabolism; heart failure

DOI:  https://doi.org/10.1161/JAHA.125.042774
Pharmacol Res. 2025 Nov 12. pii: S1043-6618(25)00457-8. [Epub ahead of print] 108032

Glycometabolic cardiac dysfunction in HFpEF: lessons from multi-omics studies.

Susanna Longo, Rocco Mollace, Viviana Casagrande, Loredana Bucciarelli, Eugenio Martelli, Rossella Menghini, Jose Manuel Fernández-Real, Massimo Federici.

  Heart Failure with preserved Ejection Fraction (HFpEF) is a complex condition that stems from intricate biochemical changes in the heart tissue. The loss of metabolic flexibility, a hallmark of unhealthy myocardium, may play a role in its progression. However, the impact of myocardial metabolic changes on the development of HFpEF and the relationship with its diverse clinical presentations remains unclear. The heterogeneous nature of HFpEF poses a challenge to research and management, highlighting the pressing need for a deeper understanding of its pathophysiology and more accurate differentiation of its phenotypes. Multi-omics, driven by artificial intelligence and machine learning, is a source of inspiration in the field of HFpEF research. This method has the potential to reveal insights into the metabolic changes and phenotypes of HFpEF that were previously inaccessible. By revealing non-traditional biomarkers that go beyond basic clinical and demographic criteria, it also inspires the development of targeted therapies for specific patient groups. This review aims to explore the current understanding of how myocardial metabolic changes and metabolic inflexibility contribute to the pathogenesis of HFpEF. By drawing on the latest multi-omics studies, it also aims to identify an omics signature for HFpEF that could be instrumental in unearthing new biomarkers for diagnosis, phenotyping, risk stratification, and the development of tailored therapies, thereby advancing personalized medicine in the field of HFpEF.

Keywords:  HFpEF; Heart failure; cardiac metabolism; metabolic inflexibility; multi-omics

DOI:  https://doi.org/10.1016/j.phrs.2025.108032
Circulation. 2025 Nov 11. 152(19): e374-e375

Response by Zile et al to Letter Regarding Article, "Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity".

Michael R Zile, Barry A Borlaug, Christopher M Kramer, Milton Packer.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.075872
Circulation. 2025 Nov 11. 152(19): e372-e373

Letter by Zhao et al Regarding Article, "Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity".

Naiqian Zhao, Xiaoyan Li, Li Wang.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.074627
BMC Cardiovasc Disord. 2025 Nov 14. 25(1): 813

SGLT2 inhibitors and left atrial function in heart failure with reduced or mildly reduced ejection fraction.

Hakan Duman, Hüseyin Durak, Mustafa Çetin, Müjgan Ayşenur Şahin, Elif Ergül, Erhan Saraçoğlu, Barış Dindar, Nadir Emlek.

   BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce cardiovascular mortality and hospitalizations in heart failure (HF). However, their effects on left atrial (LA) structure and function remain unclear, particularly in patients with reduced or mildly reduced ejection fraction (EF).
METHODS: This observational, cross-sectional study included 134 patients with HF and EF < 50%, divided into two groups: those receiving SGLT2 inhibitors (SGLT2+, n = 25) and those not receiving them (SGLT2-, n = 109). Echocardiographic measurements of LA volume index (LAVI), LA emptying fraction (LAEF), LA functional index (LAFI), and passive/active emptying fractions were obtained according to ASE/EACVI guidelines. Clinical, laboratory, and echocardiographic parameters were compared between groups, and correlations with LA indices were analyzed using multivariable linear regression.
RESULTS: The prevalence of diabetes mellitus, spironolactone use, and furosemide use was significantly higher in the SGLT2 + group (all p < 0.05). LVEF was lower (32.9 ± 6.7 vs. 38.7 ± 8.6, p = 0.002), and left ventricular volumes were larger in the SGLT2 + group, while LAFI was significantly reduced (0.12 ± 0.08 vs. 0.18 ± 0.10, p = 0.008). However, there were no significant differences in LAVI or LAEF between groups. Multivariable regression identified E/A ratio, age, and LVEF as independent determinants of LAVI; posterior wall thickness and E/A ratio for LAEF; and E/A ratio, diabetes mellitus, posterior wall thickness, and interventricular septal thickness for LAFI.
CONCLUSION: SGLT2 inhibitor use was not associated with significant improvement in LA volume or functional parameters in patients with HF and reduced or mildly reduced EF. The prognostic value of LA functions appears to be primarily influenced by diastolic dysfunction and ventricular remodeling rather than SGLT2 inhibitor therapy.

Keywords:  Heart failure; LA function.; LAVI; Left atrium; SGLT2 inhibitors

DOI:  https://doi.org/10.1186/s12872-025-05308-0
Mitochondrion. 2025 Nov 11. pii: S1567-7249(25)00094-7. [Epub ahead of print]86 102097

Intravenous mitochondrial transplantation as an adjunctive therapy for dilated cardiomyopathy.

Tuğba Varlik, Didem Algan, Öner Sönmez, Keshav K Singh, Öner Ülger, Gökhan Burçin Kubat, Jørgen Koch, Zeki Yilmaz.

  Dilated cardiomyopathy (DCM) is one of the most prevalent myocardial disorders in various animals. The underlying causes of DCM are complex and often involve multiple contributing mechanisms. Mitochondrial dysfunction has been identified as a key factor in the progression of cardiomyocyte apoptosis. We investigated whether the transplantation of healthy mitochondria improves cardiac function by enhancing the contractile function of myocytes. A 6-year-old dog with cardiomyopathy received platelet-derived, viable mitochondria from a healthy donor as adjunctive therapy alongside standard medical management. Mitochondria were isolated from platelets and administered as a single intravenous bolus at a dose of 81,125 μg/mL. This procedure was carried out under continuous ECG and vital signs monitoring. Ventricular systolic function was assessed at multiple intervals using conventional echocardiography and two-dimensional speckle tracking imaging. Our study revealed notable improvement in systolic performance as early as two hours post-transplantation of mitochondria, with enhanced contractility sustained up to 24 h. These studies suggest mitochondrial transplantation may offer a promising intervention or adjunct to conventional treatments for cardiac dysfunction. This report presents the first documented case of intravenous mitochondrial transplantation in canine DCM.

Keywords:  Dilated cardiomyopathy; Mitochondrial transplantation; Speckle tracking echocardiography; Systolic myocardial dysfunction; Translational medicine

DOI:  https://doi.org/10.1016/j.mito.2025.102097