bims-hafaim 2025-02-02 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–02–02
six papers selected by
Kyle McCommis, Saint Louis University

Posttranslational modifications in cardiac metabolic remodeling mediated by metabolites: Implications for disease pathology and therapeutic potential.
Targeting Ketone Body Metabolism Improves Cardiac Function and Hemodynamics in Patients With Heart Failure: A Systematic Review and Meta-Analysis.
Sodium-dependent glucose transporter 2 inhibitors improve heart function in patients with type 2 diabetes and heart failure.
A High-Fat Diet Induces Epigenetic 1-Carbon Metabolism, Homocystinuria, and Renal-Dependent HFpEF.
Heterogeneity across outcomes in clinical trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors in chronic heart failure: cross-sectional study.
Mitochondrial Dysfunction in HFpEF: Potential Interventions Through Exercise.

Metabolism. 2025 Jan 24. pii: S0026-0495(25)00013-7. [Epub ahead of print] 156144

Posttranslational modifications in cardiac metabolic remodeling mediated by metabolites: Implications for disease pathology and therapeutic potential.

Lifei Guo, Yuting Du, Heng Li, Ting He, Li Yao, Guodong Yang, Xuekang Yang.

  The nonenergy-producing or biomass-accumulating functions of metabolism are attracting increasing attention, as metabolic changes are gaining importance as discrete signaling pathways in modulating enzyme activity and gene expression. Substantial evidence suggests that myocardial metabolic remodeling occurring during diabetic cardiomyopathy, heart failure, and cardiac pathological stress (e.g., myocardial ischemia, pressure overload) contributes to the progression of pathology. Within the rewired metabolic network, metabolic intermediates and end-products can directly alter protein function and/or regulate epigenetic modifications by providing acyl groups for posttranslational modifications, thereby affecting the overall cardiac stress response and providing a direct link between cellular metabolism and cardiac pathology. This review provides a comprehensive overview of the functional diversity and mechanistic roles of several types of metabolite-mediated histone and nonhistone acylation, namely O-GlcNAcylation, lactylation, crotonylation, β-hydroxybutyrylation, and succinylation, as well as fatty acid-mediated modifications, in regulating physiological processes and contributing to the progression of heart disease. Furthermore, it explores the potential of these modifications as therapeutic targets for disease intervention.

Keywords:  Butyrylation; Cardiac disease; Crotonylation; Lactylation; Malonylation; Metabolites; O-GlcNAcylation; Palmitoylation; Posttranslational modification; Propionylation; Succinylation; β-Hydroxybutyrylation

DOI:  https://doi.org/10.1016/j.metabol.2025.156144
Nutr Rev. 2025 Jan 28. pii: nuae179. [Epub ahead of print]

Targeting Ketone Body Metabolism Improves Cardiac Function and Hemodynamics in Patients With Heart Failure: A Systematic Review and Meta-Analysis.

Tingting Lv, Chunyan Liu, Shitian Guo, Menglu Wu, Xiang Wang, Ziyi Zhang, Jiedong Zhou, Yiying Yao, Zeyu Shen, Juntao Yang, Shijia Sun, Zheng Liu, Jufang Chi.

   CONTEXT: The impacts of elevated ketone body levels on cardiac function and hemodynamics in patients with heart failure (HF) remain unclear.
OBJECTIVE: The effects of ketone intervention on these parameters in patients with HF were evaluated quantitatively in this meta-analysis.
DATA SOURCES: We searched the PubMed, Cochrane Library, and Embase databases for relevant studies published from inception to April 13, 2024. Ketone therapy included ketone ester and β-hydroxybutyrate intervention.
DATA EXTRACTION: Seven human studies were included for the quantitative analysis.
DATA ANALYSIS: Our results showed that ketone therapy significantly improved left ventricular ejection fraction (standardized mean difference, 0.52 [95% CI, 0.25-0.80]; I2 = 0%), cardiac output (0.84 [95% CI, 0.36-1.32]; I2 = 68%) and stroke volume (0.47 [95% CI, 0.10-0.84]; I2 = 39%), and significantly reduced systemic vascular resistance (-0.92 [95% CI, -1.52 to -0.33]; I2 = 74%) without influencing mean arterial pressure (-0.09 [95% CI: -0.40 to 0.22]; I2 = 0%) in patients with HF. Subgroup analysis revealed that the enhanced cardiac function and favorable hemodynamic effects of ketone therapy were also applicable to individuals without HF.
CONCLUSIONS: Ketone therapy may significantly improve cardiac systolic function and hemodynamics in patients with HF and in patients without HF, suggesting it may be a promising treatment for patients with HF and also a beneficial medical strategy for patients without HF or healthy individuals.

Keywords:  cardiac function and hemodynamics; heart failure; ketone body metabolism; meta-analysis

DOI:  https://doi.org/10.1093/nutrit/nuae179
World J Cardiol. 2025 Jan 26. 17(1): 100886

Sodium-dependent glucose transporter 2 inhibitors improve heart function in patients with type 2 diabetes and heart failure.

Yi-Fei Zhang, Yu-Xiang Liu, Wu-Xiao Yang.

  This article discusses the study by Grubić Rotkvić et al on the mechanisms of action of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF). T2DM and HF are highly comorbid, with a significantly increased prevalence of HF in patients with T2DM. SGLT2i exhibit potential in reducing hospitalization rates for HF and cardiovascular mortality through multiple mechanisms, including improving blood glucose control, promoting urinary sodium excretion, reducing sympathetic nervous system activity, lowering both preload and afterload on the heart, alleviating inflammation and oxidative stress, enhancing endothelial function, improving myocardial energy metabolism, and stabilizing cardiac ion homeostasis. Further research and clinical practice will help optimize the use of SGLT2i in HF patients.

Keywords:  Cardiovascular disease; Diabetic cardiomyopathy; Heart failure; Sodium-glucose cotransporter 2 inhibitors; Type 2 diabetes mellitus

DOI:  https://doi.org/10.4330/wjc.v17.i1.100886
Nutrients. 2025 Jan 08. pii: 216. [Epub ahead of print]17(2):

A High-Fat Diet Induces Epigenetic 1-Carbon Metabolism, Homocystinuria, and Renal-Dependent HFpEF.

Suresh C Tyagi.

   BACKGROUND/OBJECTIVES: Chronic gut dysbiosis due to a high-fat diet (HFD) instigates cardiac remodeling and heart failure with preserved ejection fraction (HFpEF), in particular, kidney/volume-dependent HFpEF. Studies report that although mitochondrial ATP citrate lyase (ACLY) supports cardiac function, it decreases more in human HFpEF than HFrEF. Interestingly, ACLY synthesizes lipids and creates hyperlipidemia. Epigenetically, ACLY acetylates histone. The mechanism(s) are largely unknown.
METHODS/RESULTS: One hypothesis is that an HFD induces epigenetic folate 1-carbon metabolism (FOCM) and homocystinuria. This abrogates dipping in sleep-time blood pressure and causes hypertension and morning heart attacks. We observed that probiotics/lactobacillus utilize fat/lipids post-biotically, increasing mitochondrial bioenergetics and attenuating HFpEF. We suggest novel and paradigm-shift epigenetic mitochondrial sulfur trans-sulfuration pathways that selectively target HFD-induced HFpEF. Previous studies from our laboratory, using a single-cell analysis, revealed an increase in the transporter (SLC25A) of s-adenosine-methionine (SAM) during elevated levels of homocysteine (Hcy, i.e., homocystinuria, HHcy), a consequence of impaired epigenetic recycling of Hcy back to methionine due to an increase in the FOCM methylation of H3K4, K9, H4K20, and gene writer (DNMT) and decrease in eraser (TET/FTO). Hcy is transported to mitochondria by SLC7A for clearance via sulfur metabolomic trans-sulfuration by 3-mercaptopyruvate sulfur transferase (3MST).
CONCLUSIONS: We conclude that gut dysbiosis due to HFD disrupts rhythmic epigenetic memory via FOCM and increases in DNMT1 and creates homocystinuria, leading to a decrease in mitochondrial trans-sulfuration and bioenergetics. The treatment with lactobacillus metabolites fat/lipids post-biotically and bi-directionally produces folic acid and lactone-ketone body that mitigates the HFD-induced mitochondrial remodeling and HFpEF.

Keywords:  ATP–citrate lyase; eraser and editor; folate 1-carbon metabolism; gene writer; heart failure; kidney; morning heart attacks

DOI:  https://doi.org/10.3390/nu17020216
J Clin Epidemiol. 2025 Jan 22. pii: S0895-4356(25)00018-6. [Epub ahead of print] 111685

Heterogeneity across outcomes in clinical trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors in chronic heart failure: cross-sectional study.

Fran Šaler, Marin Viđak, Ružica Tokalić, Livia Puljak.

   OBJECTIVES: This study aimed to analyze the outcomes, outcome domains, and prevalence of the use of clinical outcome endpoints (COE) in clinical trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors for chronic heart failure (CHF) registered on ClinicalTrials.gov and compare them to COE for cardiovascular trials.
STUDY DESIGN AND SETTING: We conducted a cross-sectional methodological study. Trials and trial outcomes were extracted from ClinicalTrials.gov, classified, and analyzed. For pivotal trials, registrations were compared with matching publications and supplementary documentation. The adherence of outcomes in pivotal clinical trials to COE developed by the European Society of Cardiology (ESC) was checked.
RESULTS: In 71 included trials we found 170 individual clinical outcomes and divided them into 11 groups (10 clinical outcome groups, and ESC COE). Heart failure with reduced ejection fraction (HFrEF) was analyzed in 33 (46%) trials, and heart failure with preserved ejection fraction (HFpEF) in 25% of trials. ESC COE outcomes were used in less than 30% of trials, and only in 9 as primary outcomes (13%). Trials included 59 different biomarker endpoints. Patient-reported outcomes were highly heterogeneous, utilizing various non-validated questionnaires. All five pivotal trials used primary outcomes from ESC COE. The adherence of pivotal trials to the ESC COE was moderately high, with insufficient data on dyspnea and heart failure events such as intensification of diuretic therapy. All pivotal trials had at least one change in study protocol at one point during the trial, in outcome measures, statistical model, enrollment, or trial duration.
CONCLUSIONS: Outcomes used in CHF trials of SGLT2 inhibitors were highly heterogeneous. Core outcome sets developed especially for CHF were underutilized. Standardization of outcomes is needed in the CHF field to enable between-trial comparisons and evidence syntheses.

Keywords:  SGLT2 inhibitors; chronic heart failure; clinical endpoints; outcomes

DOI:  https://doi.org/10.1016/j.jclinepi.2025.111685
J Cardiovasc Transl Res. 2025 Jan 25.

Mitochondrial Dysfunction in HFpEF: Potential Interventions Through Exercise.

Xinxin Cui, Michail Spanos, Cuimei Zhao, Wensi Wan, Caiyue Cui, Lijun Wang, Junjie Xiao.

  HFpEF is a prevalent and complex type of heart failure. The concurrent presence of conditions such as obesity, hypertension, hyperglycemia, and hyperlipidemia significantly increase the risk of developing HFpEF. Mitochondria, often referred to as the powerhouses of the cell, are crucial in maintaining cellular functions, including ATP production, intracellular Ca2+ regulation, reactive oxygen species generation and clearance, and the regulation of apoptosis. Exercise plays a vital role in preserving mitochondrial homeostasis, thereby protecting the cardiovascular system from acute stress, and is a fundamental component in maintaining cardiovascular health. In this study, we review the mitochondrial dysfunction underlying the development and progression of HFpEF. Given the pivotal role of exercise in modulating cardiovascular diseases, we particularly focus on exercise as a potential therapeutic strategy for improving mitochondrial function. Graphical abstract Note: This picture was created with BioRender.com.

Keywords:  Exercise; Heart failure with preserved ejection fraction; Mitochondria; Mitochondrial dynamics; Oxidative stress

DOI:  https://doi.org/10.1007/s12265-025-10591-5