bims-hafaim 2025-12-14 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–12–14
nine papers selected by
Kyle McCommis, Saint Louis University

Comparative analysis of metabolic and functional cardiac alterations in diet- and genetically induced mouse models of cardiac dysfunction.
The toxic effects of doxorubicin and trastuzumab on cardiac metabolic reprogramming are associated with impaired mitochondrial dynamics balance.
Targeting Metabolic Dysfunction and Inflammation with Sotagliflozin Reverses Diastolic Dysfunction in Experimental HFpEF.
Succinate-GPR91 signaling promotes cardiomyocyte metabolic reprogramming and NAD+ production to alleviate HFpEF.
Aging and metabolism in HFpEF: Pathophysiology and therapeutic implications.
Metabolic Modulation in Dilated Cardiomyopathy: From Pathophysiology to Therapy.
Metabo-epigenetic circuits of heart failure: chromatin-modifying enzymes as determinants of metabolic plasticity.
Cyclophilin B deficiency enhances myocardial energy synthesis and protects against heart failure in preclinical models.
Cirsiliol alleviates diabetic cardiomyopathy by inhibiting oxidative stress and improving energy metabolism through the PPAR-α/AMPK pathway.

FEBS J. 2025 Dec 12.

Comparative analysis of metabolic and functional cardiac alterations in diet- and genetically induced mouse models of cardiac dysfunction.

Christiane Ott, Patricia Baumgarten, Thorsten Henning, Daniela Weber, Iwona Wallach, Jana Grune, Ulrich Kintscher, Hermann-Georg Holzhütter, Tilman Grune, Nikolaus Berndt.

  Cardiac metabolism is highly adaptive, and distinct maladaptive remodeling processes may contribute to the development of cardiac dysfunction. Here, we compared the metabolic, structural, and functional adaptations of two murine models: C57BL/6J mice fed a high-fat, carbohydrate-free diet and New Zealand Obese mice maintained on a standard diet. Cardiac function was assessed by echocardiography, plasma metabolite profiles were analyzed, and cardiac proteomes were quantified by mass spectrometry. Proteomic data were computationally integrated into a kinetic model of cardiac central metabolism (CARDIOKIN1) to predict changes in substrate utilization and ATP production capacities under physiological nutrient conditions. Diet-induced metabolic stress led to cardiac dysfunction with preserved ejection fraction, characterized by mitochondrial dysfunction, impaired ATP production, inflammation, and reduced cardiac mass. Conversely, genetically induced obesity resulted in cardiac impairment with reduced ejection fraction associated with mild fibrosis, maintained ATP production, and substrate switching favoring fatty acid utilization. Proteomic and computational analyses revealed a coordinated downregulation of metabolic networks involved in oxidative phosphorylation, substrate transport, and energy production in both models, but with distinct profiles of metabolic inflexibility and mitochondrial efficiency. This study provides insights of how dietary versus genetic metabolic stress reprograms cardiac metabolism and structure, offering mechanistic insights into the diverse pathways leading to cardiac dysfunction. These insights may guide future strategies for metabolic intervention in heart failure subtypes.

Keywords:  cardiac dysfunction; cardiac metabolism; genetically induced obesity; high‐fat diet; metabolic adaptation

DOI:  https://doi.org/10.1111/febs.70362
Food Chem Toxicol. 2025 Dec 09. pii: S0278-6915(25)00663-5. [Epub ahead of print] 115895

The toxic effects of doxorubicin and trastuzumab on cardiac metabolic reprogramming are associated with impaired mitochondrial dynamics balance.

Chanisa Thonusin, Chayodom Maneechote, Siriporn C Chattipakorn, Nipon Chattipakorn.

  The toxicity of doxorubicin and trastuzumab can lead to heart failure. Its pathophysiology is correlated with cardiac metabolic reprogramming. Therefore, we investigated the effects of doxorubicin and trastuzumab on cardiac metabolic reprogramming. Since mitochondrial dynamics imbalance is associated with cardiotoxicity, we evaluated the effects of restoring balance of mitochondrial dynamics on reducing cardiotoxicity. Male Wistar rats received either vehicle, 6 doses of 3 mg/kg of doxorubicin, or 4 mg/kg/day of trastuzumab. Doxorubicin-treated rats and trastuzumab-treated rats were also co-treated with either vehicle, 1.2 mg/kg/day of MDiVi1 (mitochondrial fission inhibitor), or 2 mg/kg/day of M1 (mitochondrial fusion promoter). The treatment duration was 30 and 7 days for doxorubicin and trastuzumab studies, respectively. Thereafter, cardiac function was determined. The rats were then euthanized to collect cardiac ventricular tissues for targeted metabolomics via liquid chromatography coupled with mass spectrometry. We found that doxorubicin and trastuzumab caused increased glycolysis, increased ketone body metabolism, decreased fatty acid utilization, decreased succinate oxidation, and decreased ATP production. These changes were more severe in doxorubicin-treated rats. Restoring mitochondrial dynamics balance by MDiVi1 or M1 improved cardiac metabolic reprogramming. These novel findings highlighted the toxic effects of doxorubicin and trastuzumab on cardiac metabolic reprogramming and their association with mitochondrial dynamics. Also, metabolomics might be used as a tool for treatment monitoring in doxorubicin- and trastuzumab-induced cardiotoxicity.

Keywords:  Cardiotoxicity; Doxorubicin; Heart failure; Metabolic reprogramming; Mitochondrial dynamics; Trastuzumab

DOI:  https://doi.org/10.1016/j.fct.2025.115895
bioRxiv. 2025 Dec 01. pii: 2025.11.27.691021. [Epub ahead of print]

Targeting Metabolic Dysfunction and Inflammation with Sotagliflozin Reverses Diastolic Dysfunction in Experimental HFpEF.

Parisa Shabani, Tahra Luther, Rajesh Chaudhary, Anand P Singh, Afnan Alzamrooni, Olga Grushko, Nathan Levine, Rachel Lopez-Schenk, Sascha N Goonwardena, Bertram Pitt, Ahmed Abdel-Latif.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and strongly associated with cardiometabolic comorbidities including obesity, hypertension, and metabolic dysfunction. While SGLT2 inhibitors have demonstrated clinical benefits in HFpEF, the mechanisms underlying dual SGLT1/2 inhibition remain incompletely understood.
METHODS: We utilized a murine model of cardiometabolic HFpEF induced by high-fat diet combined with L-NAME administration. Following disease establishment, mice received sotagliflozin (30 mg/kg) or vehicle for 10 weeks. Comprehensive assessments included echocardiography, indirect calorimetry, cardiac metabolomics, bulk RNA sequencing with cell-type deconvolution, and high-dimensional immune profiling by flow cytometry and CyTOF.
RESULTS: Sotagliflozin significantly attenuated weight gain and improved glucose tolerance without normalizing blood pressure. Metabolic cage analyses revealed a sustained reduction in respiratory exchange ratio, indicating enhanced fatty acid oxidation, corroborated by elevated cardiac acylcarnitine intermediates including palmitoylcarnitine and dodecanoylcarnitine. Echocardiography demonstrated that sotagliflozin protected against diastolic dysfunction, normalizing isovolumic relaxation time and E/e' ratio while reducing left ventricular mass and myocardial fibrosis. Transcriptomic profiling revealed upregulation of mitochondrial fatty acid β-oxidation pathways and suppression of inflammatory signaling cascades including IL-1 processing and TLR pathways. Flow cytometric analysis demonstrated reduced cardiac infiltration of neutrophils, CCR2+ inflammatory monocytes/macrophages, and IL-1β-expressing immune cells. Splenic immune cell expansion characteristic of systemic inflammation was similarly attenuated.
CONCLUSIONS: Dual SGLT1/2 inhibition with sotagliflozin exerts coordinated cardiometabolic benefits in experimental HFpEF through metabolic reprogramming toward enhanced lipid utilization and suppression of cardiac and systemic inflammation. These findings establish that sotagliflozin targets the intertwined metabolic-inflammatory axis central to HFpEF pathogenesis, providing mechanistic insight into the therapeutic efficacy of dual SGLT inhibition in cardiometabolic heart failure.

DOI: https://doi.org/10.1101/2025.11.27.691021
Cardiovasc Diabetol. 2025 Dec 06.

Succinate-GPR91 signaling promotes cardiomyocyte metabolic reprogramming and NAD+ production to alleviate HFpEF.

Yumeng Jia, Wenhui Niu, Lu Liu, Qun Zhang, Dingwei Li, Tangyu Dai, Jie Du, Lei Wang.

   BACKGROUND: Disrupted cardiomyocyte energy metabolism is a hallmark of heart failure with preserved ejection fraction (HFpEF). Succinate, a key intermediate of the tricarboxylic acid cycle, is markedly decreased in HFpEF myocardium. In addition to its metabolic role, succinate functions as a signaling molecule that activates GPR91 to regulate metabolic and immune pathways. However, the precise contributions and mechanisms of cardiomyocyte succinate-GPR91 signaling in HFpEF pathogenesis remain incompletely understood.
METHODS: HFpEF models were established in wild-type (WT), global GPR91 knockout (Gpr91-/-), and cardiomyocyte-specific GPR91 knockout (Gpr91ΔCM) mice, with or without succinate supplementation. Cardiac structure, function, and metabolic phenotypes were assessed using echocardiography, histology, and molecular assays. Transcriptome sequencing of myocardial tissues was performed to identify pathways regulated by succinate-GPR91 signaling. Mechanistic studies in human AC16 cardiomyocytes were conducted to validate pathway regulation and clarify downstream molecular mechanisms. Additionally, rescue experiments were performed to confirm the functional relevance of succinate-GPR91 signaling in cardiomyocyte metabolism and HFpEF progression.
RESULTS: Cardiac succinate levels and GPR91 expression were markedly decreased in HFpEF mice. Succinate supplementation restored systemic metabolism, improved diastolic function, and attenuated myocardial hypertrophy and fibrosis in WT HFpEF mice, whereas these protective effects were abolished in both Gpr91-/- and Gpr91ΔCM mice. Transcriptomic analysis demonstrated that succinate activated AMPK signaling and enriched pathways related to glucose-lipid metabolism and NAD+ biosynthesis in Gpr91fl/fl but not in Gpr91ΔCM hearts. Mechanistically, succinate enhanced AMPK phosphorylation and NAD+ production via Gq-mediated signaling, thereby promoting cardiomyocyte metabolic reprogramming.
CONCLUSION: These findings identify the succinate-GPR91 axis as a critical regulator of cardiometabolic homeostasis and a potential therapeutic target in HFpEF.

Keywords:  AMPK; Cardiomyocyte; GPR91; HFpEF; NAD+ ; Succinate

DOI:  https://doi.org/10.1186/s12933-025-03030-x
Metabolism. 2025 Dec 04. pii: S0026-0495(25)00329-4. [Epub ahead of print] 156460

Aging and metabolism in HFpEF: Pathophysiology and therapeutic implications.

Min Ye, Shenghui Feng, Zixuan Xu, Wenfeng He, Chen Liu, Wengen Zhu.

  Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as an age-predominant syndrome characterized by diastolic dysfunction despite preserved systolic performance. In the aged myocardium, fatty acid oxidation capacity declines, while glycolytic flux increases; however, impaired pyruvate oxidation limits mitochondrial glucose oxidation, resulting in suboptimal ATP yield per oxygen molecule and worsening energetic inefficiency. Mitochondrial deficits, marked by reduced biogenesis, NAD+ depletion related to reduced sirtuin activity and consequent hyperacetylation of oxidative enzymes, and impaired electron-transport capacity, further diminish bioenergetic reserve and elevate reactive oxygen species generation. Concurrently, inflammaging and proteostatic collapse promote chronic low-grade inflammation, misfolded protein accumulation, and myocardial fibrosis, collectively contributing to increased ventricular stiffness and progressive HFpEF development. Therapeutic strategies targeting these interconnected pathways show considerable promise. Preclinical studies suggest that interventions such as NAD+ precursor supplementation, mTORC1 inhibition, and β-hydroxybutyrate administration can ameliorate HFpEF-like phenotypes by improving mitochondrial efficiency and reducing inflammation. SGLT2 inhibitors and GLP-1 receptor agonists confer clinically proven benefits in HFpEF, likely via systemic metabolic reprogramming toward more oxygen-efficient substrates and attenuation of inflammation. This review underscores the critical role of aging-associated metabolic and mitochondrial derangements in HFpEF pathogenesis and highlights mechanistically tailored interventions as the next frontier in managing this challenging, age-related syndrome.

Keywords:  Cardiac aging; Heart failure with preserved ejection fraction; Metabolic remodeling; Mitochondrial dysfunction; Therapeutic targets

DOI:  https://doi.org/10.1016/j.metabol.2025.156460
Rev Cardiovasc Med. 2025 Nov;26(11): 45518

Metabolic Modulation in Dilated Cardiomyopathy: From Pathophysiology to Therapy.

Xiang Nie, Zhibing Lu.

  This review aims to synthesize current evidence on the role of cardiac energy metabolism in the pathogenesis of dilated cardiomyopathy (DCM), with a focus on myocardial blood flow, substrate utilization, genetic and metabolic pathways, and potential energy-targeted therapeutic strategies. DCM involves structural and functional impairments of the myocardium, often linked to genetic mutations (e.g., in titin (TTN) and lamin) or acquired factors, including infection, alcohol, drugs, and endocrine disorders. Moreover, the disruption of cardiac energy homeostasis is central to the pathogenesis of DCM, characterized by compromised energy supply, altered substrate metabolism, and reduced adenosine triphosphate (ATP) production, all of which collectively contribute to contractile dysfunction and disease progression. Emerging evidence indicates that impaired myocardial energetics, including reduced coronary blood flow, shifts in fuel utilization, and dysregulation of energy metabolic pathways, are hallmark features of DCM. Nonetheless, energy deficiency is increasingly being recognized as a key driver of DCM development and heart failure. Cardiac energy metabolic disruption is intimately involved in the pathophysiology of DCM and represents a promising target for novel therapeutic interventions. Current management strategies often overlook metabolic aspects; therefore, this review highlights the need to integrate energy-based approaches into the treatment paradigm for DCM.

Keywords:  dilated cardiomyopathy; energy supply and metabolism; genetic mutation; myocardial blood flow

DOI:  https://doi.org/10.31083/RCM45518
EMBO Mol Med. 2025 Dec 11.

Metabo-epigenetic circuits of heart failure: chromatin-modifying enzymes as determinants of metabolic plasticity.

Mark E Pepin, Xuemin Gong, Almut Schulze, Johannes Backs.

  Metabolic adaptations are a functional requirement for the heart to accommodate its broad range of physiologic operating conditions. It is increasingly recognized that persistent and exaggerated metabolic alterations precede adverse cardiac remodeling leading to heart failure. These metabolic shifts are coupled with changes in cardiac gene expression, driven in part by chromatin-modifying enzymes, which have recently been identified as both sensors and transducers of metabolic stress and gene regulatory networks, respectively. This review synthesizes the latest evidence implicating chromatin-modifying enzymes as key regulators of metabolic reprogramming in the heart, providing a framework to understand how metabolic stressors are incorporated as epigenetic modifications that regulate cardiac gene expression. We propose a model of 'metabo-epigenetic circuitry' within which energy metabolic perturbations drive transcriptional and epigenetic changes that ultimately contribute to cardiac dysfunction. Although many nodes in these circuits remain unidentified, this viewpoint opens new avenues for investigating chromatin-modifying enzymes as therapeutic targets to halt the metabolic programs that promote heart failure.

Keywords:  Cardiomyopathy; Epigenetics; Heart Failure; Metabolism; Signaling

DOI:  https://doi.org/10.1038/s44321-025-00343-y
BMC Med. 2025 Dec 07.

Cyclophilin B deficiency enhances myocardial energy synthesis and protects against heart failure in preclinical models.

Xiao Zong, Xierenayi Tudi, Qian Yang, Lingfang Zhuang, Roubai Pan, Qin Fan, Rong Tao.

   BACKGROUND: Heart failure (HF) represents the end stage of cardiovascular diseases with high mortality and limited treatment options. Cyclophilin B (CypB), known mainly as an endoplasmic reticulum chaperone, has been implicated in cardiovascular diseases. But the role of CypB in HF remains unclear.
METHODS: Transverse aortic constriction (TAC) surgery on mice in vivo was conducted to model cardiac hypertrophy (CH) and HF, and angiotensin II (Ang II) was applied to neonatal rat cardiomyocytes in vitro to mimic cardiomyocyte hypertrophy. The effects of CypB deficiency on CH/HF were evaluated by echocardiography, tissue staining, and molecular expression assays. The mechanism of CypB action was elucidated by RNA sequencing, bioinformatics analysis, mitochondrial function assay, immunofluorescence staining, glucose uptake assay, PET/CT scan, transcription factor analysis, dual luciferase reporter assay, Cut&Run-qPCR assay, STAT3 inhibitor, and overexpression virus.
RESULTS: Increased expression of CypB has been observed in hypertrophied and failing hearts. CypB deficiency improves cardiac function, reduces hypertrophy after TAC surgery, and attenuates Ang II-induced cardiomyocyte hypertrophy. Mechanistically, CypB deletion increases AMPK phosphorylation, enhances the expression of glucose transporter type 1 (GLUT1), glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and downstream signaling molecules, thereby promoting cardiac glucose catabolism and mitochondrial function. STAT3 transcriptionally activates CypB expression, STAT3 inhibition ameliorates TAC-induced heart failure, and CypB deficiency reverses STAT3 overexpression-induced HF.
CONCLUSIONS: CypB deficiency ameliorates CH and HF by enhancing cardiac energy production, providing a potential therapeutic target for CH and HF.

Keywords:  Cardiac hypertrophy; Cyclophilin B; Heart failure; Metabolism; STAT3

DOI:  https://doi.org/10.1186/s12916-025-04563-4
Sci Rep. 2025 Dec 11.

Cirsiliol alleviates diabetic cardiomyopathy by inhibiting oxidative stress and improving energy metabolism through the PPAR-α/AMPK pathway.

Jing Tao, Siqi Liu, Yunzhi Ling, Hanlin Bai, Lei Liu, Ru Yu, Guangling Li.

  Diabetic cardiomyopathy (DCM) is a core cause of heart failure in diabetic patients, with major pathological features including myocardial energy metabolism disorders, mitochondrial dysfunction, oxidative stress, and inflammatory cascades. This study investigates the mechanism by which the flavonoid compound Cirsiliol improves DCM by regulating the peroxisome proliferator-Activated receptor α (PPAR-α)/AMP-activated protein kinase (AMPK) signaling pathway. Using a high-glucose-treated H9C2 myocardial cell model and a streptozotocin-induced diabetic mouse model, the results show that Cirsiliol can dose-dependently increase myocardial cell survival, inhibit high-glucose-induced apoptosis, and significantly improve cardiac function in diabetic mice. Mechanistic studies indicate that Cirsiliol activates the PPAR-α/AMPK pathway, upregulates the expression of key fatty acid oxidation enzymes carnitine palmitoyltransferase 1 (CPT1) and p-acetyl-CoA carboxylase (ACC), restores mitochondrial membrane potential, reduces lipid peroxidation product malondialdehyde (MDA) levels, enhances superoxide dismutase activity, and inhibits the release of inflammatory factors such as Interleukin 6 (IL-6) and Tumor Necrosis Factor α (TNF-α). This study elucidates that Cirsiliol intervenes in energy metabolism imbalance, oxidative stress, and inflammatory responses through multiple targets, providing a new strategy for the treatment of DCM.

Keywords:  Cell apoptosis; Cirsiliol; Diabetic cardiomyopathy; Inflammatory response; Oxidative stress; PPAR-α/AMPK

DOI:  https://doi.org/10.1038/s41598-025-32157-w