bims-hafaim 2025-06-15 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–06–15
eight papers selected by
Kyle McCommis, Saint Louis University

Long-lasting metabolic impairment in the failing heart: epigenetic memories at play.
PFKFB2 is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
Nicotinamide Adenine Dinucleotide Supplementation to Alleviate Heart Failure: A Mitochondrial Dysfunction Perspective.
Incretin-based therapies for individuals with obesity and heart failure with mildly reduced or preserved ejection fraction: A systematic review and meta-analysis of randomized controlled trials.
ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium.
Structural and functional characterization of the cardiac mitochondria-associated reticular membranes in the ob/ob mouse model.
FMO2 Prevents Pathological Cardiac Hypertrophy by Maintaining the ER-Mitochondria Association Through Interaction With IP3R2-Grp75-VDAC1.
Ketogenic capacity of the heart determines the outcome of heart failure.

Epigenetics. 2025 Dec;20(1): 2515430

Long-lasting metabolic impairment in the failing heart: epigenetic memories at play.

Sarah Costantino, Francesco Paneni.

  Understanding the factors involved in myocardial recovery after unloading is of utmost importance to unveil new therapies in patients with heart failure (HF). Lack of myocardial recovery might be explained by long-lasting molecular alterations which persist despite normalization of cardiac stress. In this issue of Epigenetics, Roth et al. present an elegant translational study addressing this important aspect at the molecular level. By leveraging a mouse model of reversible transverse aortic constriction (rTAC) and human LV samples from HF patients undergoing LVAD therapy, the authors show that cardiac unloading is associated with a persistent deregulation of transcriptional programmes implicated in mitochondrial respiration, fatty acid and acyl-CoA metabolism, suggesting a long-lasting metabolic deterioration of the failing heart. Of interest, the authors identified several chromatin remodellers (Hdac4, Smarca2, and Brd4) potentially explaining the observed transcriptional alterations. Taken together, these novel findings suggest that 'DNA forgives but does not forget,' thus leaving an epigenetic scar which hampers the recovery of the failing heart after unloading. Disentangling the epigenetic factors involved in such 'transcriptional memory' may set the stage for new interventions resetting the cardiomyocyte transcriptome and myocardial energetics thus fostering a true myocardial recovery in HF.

Keywords:  Heart failure; LVAD; chromatin; epigenetics; metabolism; mitochondria

DOI:  https://doi.org/10.1080/15592294.2025.2515430
bioRxiv. 2025 May 27. pii: 2025.05.26.656235. [Epub ahead of print]

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 post-translational modification O-GlcNAcylation are affected in cKO mice in response to fasting or pharmacologic stimulation.
Methods: cKO and litter-matched controls (CON) were sacrificed 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 CPT1 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.
Graphic Abstract:
Research Perspective: This study raises and answers three key questions: how PFKFB2 contributes to cardiac mitochondrial metabolic flexibility, how post-prandial status regulates O-GlcNAcylation in a PFKFB2-dependent manner, and how altered cardiac glucose use impacts systemic glucose homeostasis under stress.These findings highlight a novel role for nutrient state in regulating cardiac metabolism, and especially O-GlcNAcylation, with PFKFB2 loss.Future studies should investigate whether reducing O-GlcNAcylation through fasting is sufficient to ameliorate pathological changes observed in the absence of PFKFB2.

DOI: https://doi.org/10.1101/2025.05.26.656235
Nutrients. 2025 May 29. pii: 1855. [Epub ahead of print]17(11):

Nicotinamide Adenine Dinucleotide Supplementation to Alleviate Heart Failure: A Mitochondrial Dysfunction Perspective.

Fan Yu, Huiying Zhao, Lu Luo, Wei Wu.

  Heart failure represents the terminal stage in the development of many cardiovascular diseases, and its pathological mechanisms are closely related to disturbances in energy metabolism and mitochondrial dysfunction in cardiomyocytes. In recent years, nicotinamide adenine dinucleotide (NAD+), a core coenzyme involved in cellular energy metabolism and redox homeostasis, has been shown to potentially ameliorate heart failure through the regulation of mitochondrial function. This review systematically investigates four core mechanisms of mitochondrial dysfunction in heart failure: imbalance of mitochondrial dynamics, excessive accumulation of reactive oxygen species (ROS) leading to oxidative stress injury, dysfunction of mitochondrial autophagy, and disturbance of Ca2+ homeostasis. These abnormalities collectively exacerbate the progression of heart failure by disrupting ATP production and inducing apoptosis and myocardial fibrosis. NAD+ has been shown to regulate mitochondrial biosynthesis and antioxidant defences through the activation of the deacetylase family (e.g., silent information regulator 2 homolog 1 (SIRT1) and SIRT3) and to increase mitochondrial autophagy to remove damaged mitochondria, thus restoring energy metabolism and redox balance in cardiomyocytes. In addition, the inhibition of NAD+-degrading enzymes (e.g., poly ADP-ribose polymerase (PARP), cluster of differentiation 38 (CD38), and selective androgen receptor modulators (SARMs)) increases the tissue intracellular NAD+ content, and supplementation with NAD+ precursors (e.g., β-nicotinamide mononucleotide (NMN), nicotinamide riboside, etc.) also significantly elevates myocardial NAD+ levels to ameliorate heart failure. This study provides a theoretical basis for understanding the central role of NAD+ in mitochondrial homeostasis and for the development of targeted therapies for heart failure.

Keywords:  ATP; heart failure; mitochondrial dysfunction; nicotinamide adenine dinucleotide; redox

DOI:  https://doi.org/10.3390/nu17111855
Diabetes Obes Metab. 2025 Jun 11.

Incretin-based therapies for individuals with obesity and heart failure with mildly reduced or preserved ejection fraction: A systematic review and meta-analysis of randomized controlled trials.

Thomaz Alexandre Costa, Nicole Felix, Gabriel Cavalcante Lima Chagas, Santiago Teran, Madelyn Boslough, Vrushali Shelar, Matthew M Y Lee, Ambarish Pandey, Marconi Abreu, Darren K McGuire, Josephine Harrington.

   AIMS: Obesity is a major risk factor for heart failure with mildly reduced or preserved ejection fraction (HFpEF). This meta-analysis of randomised clinical trials (RCTs) evaluated the effects of incretin-based therapies (IBTs), including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 RAs, on clinical outcomes in individuals with the obesity-HFpEF phenotype.
MATERIALS AND METHODS: A systematic search of PubMed, EMBASE and Web of Science through December 2024 identified RCTs comparing IBTs with placebo in patients with HFpEF and obesity. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were pooled for binary outcomes, and estimated differences (EDs) for continuous outcomes, using an inverse variance random-effects model.
RESULTS AND CONCLUSIONS: Six RCTs with 7282 participants (50.3% receiving IBTs) were included. IBTs reduced the risk of cardiovascular death or worsening HF (HR 0.74; 95% CI 0.63-0.88; I2 = 0%), worsening HF events (HR 0.62; 95% CI 0.47-0.81; I2 = 16%) and all-cause mortality (OR 0.81; 95% CI 0.67-0.99; I2 = 0%) compared to placebo. No significant difference was found in cardiovascular mortality alone. IBTs also improved quality of life, functional status, systolic blood pressure and weight loss in patients with obesity-HFpEF.

Keywords:  HFpEF; glucagon‐like peptide‐1 receptor agonists; glucose‐dependent insulinotropic polypeptide; heart failure; obesity

DOI:  https://doi.org/10.1111/dom.16512
JACC Basic Transl Sci. 2025 Jun 10. pii: S2452-302X(25)00221-9. [Epub ahead of print]10(7): 101301

ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium.

Mariam Meddeb, Navid Koleini, Mohammad Keykhaei, Ting Liu, Marcus Rhodehamel, Lorena Mandarano, Farnaz Farshidfar, Liang Zhao, Seoyoung Kwon, Gizem Keceli, Ismayil Ahmet, Nazareno Paolocci, Virginia Hahn, Kavita Sharma, Erika L Pearce, David A Kass.

  ATP-citrate lyase (ACLY) regulates lipogenesis and cell proliferation, and forms a cytosolic TCA-bypass circuit impacting NADH. We show that acute and chronic ACLY inhibition in cardiomyocytes depresses the NAD+/NADH ratio by increasing mitochondrial NADH. Acute suppression causes dose-dependent cytotoxicity, but at low doses augments aerobic respiration without impeding myocyte function. ACLY is reduced in human failing myocardium, and mice with myocardial or myocyte ACLY knockdown display mildly depressed function, particularly after pressure-overload, and exertional limitations. NAD+ enhancement ameliorates dysfunction/toxicity from ACLY inhibition. These results reveal that ACLY intrinsically regulates cardiac NAD+/NADH balance and respiration, which can affect rest and reserve heart function.

Keywords:  TCA cycle; heart disease; metabolism; myocardium; redox; reductive stress

DOI:  https://doi.org/10.1016/j.jacbts.2025.04.015
J Mol Cell Cardiol Plus. 2025 Jun;12 100453

Structural and functional characterization of the cardiac mitochondria-associated reticular membranes in the ob/ob mouse model.

Hala Guedouari, Maya Dia, Juliette Geoffray, Camille Brun, Florentin Moulin, Lucas Givre, Lucid Belmudes, Christelle Leon, Stephanie Chanon, Jingwei Ji-Cao, Christophe Chouabe, Sylvie Ducreux, Claire Crola Da Silva, Ludovic Gomez, Yohann Couté, Helene Thibault, Jennifer Rieusset, Melanie Paillard.

  Type 2 diabetes (T2D) and obesity strongly lead to diabetic cardiomyopathy (DCM). The involvement of mitochondria-associated reticular membranes (MAMs), a signaling hub in the cardiomyocyte, starts to be demonstrated in T2D-related metabolic disorders. We recently discovered a cardiac MAM Ca2+ uncoupling in a high-fat high-sucrose diet (HFHSD)-induced mouse model of DCM. To better determine the role of MAMs in the progression of DCM, we here aimed to characterize the proteomic composition and function of the cardiac MAMs of another obesogenic T2D mouse model, the leptin-deficient ob/ob mouse. 12-week old male C57Bl6-N ob/ob mice displayed strain rate dysfunction and concentric remodeling, while no change was observed in fractional shortening or diastolic function. Increased lipid deposition but no fibrosis was measured in the ob/ob heart compared to WT. Electron microscopy analysis revealed that cardiac MAM length and width were similar between both groups. A trend towards an increased MAM protein content was measured in the ob/ob heart. MAM proteome analyses showed mainly increased processes in ob/ob hearts: cellular response to stress, lipid metabolism, ion transport and membrane organization. Functionally, MAM-driven Ca2+ fluxes were unchanged but hypoxic stress induced a cell death increase in the ob/ob cardiomyocyte. Mitochondrial respiration, cardiomyocyte shortening, ATP and ROS content were similar between groups. To conclude, at that age, while being strongly hyperglycemic and insulin-resistant, the ob/ob mouse model rather displays a modest DCM without strong changes in MAMs: preserved structural and functional MAM Ca2+ coupling but increased response to stress.

Keywords:  Database; Diabetic cardiopathy; ERMCs; MERCs; Mitochondrial calcium uniporter; SR-mitochondria coupling

DOI:  https://doi.org/10.1016/j.jmccpl.2025.100453
Circulation. 2025 Jun 10. 151(23): 1667-1685

FMO2 Prevents Pathological Cardiac Hypertrophy by Maintaining the ER-Mitochondria Association Through Interaction With IP3R2-Grp75-VDAC1.

Changchen Xiao, Chao Wang, Jingyi Wang, Xianpeng Wu, Changle Ke, Jinliang Nan, Hao Ding, Yinghui Xu, Yanna Shi, Jing Zhao, Cheng Ni, Qingnian Liu, Jiamin Li, Shuyuan Sheng, Hua Chen, Jiayue Cai, Tonghui Zhao, Jinghai Chen, Qiming Sun, Bin Zhou, Jian'an Wang, Wei Zhu, Xinyang Hu.

   BACKGROUND: Cardiac hypertrophy, as an important pathological change, contributes to heart failure. Recent studies indicate that the mitochondria-associated endoplasmic reticulum membranes (MAMs) play key roles in this pathological process. However, the molecular mechanism remains unclear. This study aims to elucidate the effects and mechanisms of MAM-resident FMO2 (flavin-containing monooxygenase 2) in cardiac hypertrophy and heart failure.
METHODS: We performed bulk RNA-sequencing analysis using heart tissue from patients with cardiac hypertrophy and carried out MAM-targeted mass spectrometry analysis using heart tissue from a mouse model of pathological cardiac hypertrophy. In vitro cell culture using neonatal rat cardiomyocytes was used to study how MAMs formation affected cardiomyocyte functions. By generating different genetic mouse models combined with using adeno-associated virus 9 under the cardiac troponin T promoter techniques, we further investigated and confirmed the effects of MAM structure changes on cardiac hypertrophy.
RESULTS: We detected an unexpected component of MAMs structure, which was the FMO2, an endoplasmic reticulum-resident protein. FMO2 levels decreased during pathological cardiac hypertrophy. The deletion and overexpression of FMO2 can either worsen or prevent the pathological heart failure progression in vivo, respectively. Our data further demonstrated that FMO2 localizes to MAM structure, where it binds to inositol 1,4,5-trisphosphate type 2 receptor (IP3R2) as a component of the IP3R2-Grp75 (glucose-regulated protein 75)-VDAC1 (voltage-dependent anion channel protein 1) complex, maintaining endoplasmic reticulum-mitochondria contact and regulating mitochondrial Ca2+ signaling for bioenergetics. Last, we showed that a synthetic peptide-enhancing endoplasmic reticulum-mitochondria contact promoted Ca2+ transfer and prevented pathological cardiac hypertrophy.
CONCLUSIONS: Our findings reveal a key role of FMO2 in myocardial hypertrophy and that FMO2 plays a pivotal role in maintaining MAM structure and function, which may represent a novel mechanism and therapeutic target for cardiac hypertrophy and heart failure.

Keywords:  hypertrophy; mitochondria; mitochondria associated membranes

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.072661
Nat Cardiovasc Res. 2025 Jun 06.

Ketogenic capacity of the heart determines the outcome of heart failure.

Gerburg Schwaerzer.

DOI: https://doi.org/10.1038/s44161-025-00676-4