bims-hafaim 2026-07-19 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2026–07–19
seven papers selected by
Kyle McCommis, Saint Louis University

Sirtuins at the Interface of Glucose Metabolism, Diabetes, and Heart Failure: Metabolic Sensing in Cardiometabolic Disease.
Bioenergetics-Driven Extracellular Vesicle Therapies for Heart Failure: From Preclinical Insights to Regenerative Translation.
Circulating β-Hydroxybutyrate in Glycemic Progression and Diabetic Cardiomyopathy: Adaptive Signal or Maladaptive Substrate?
Metabolite sensing in cardiometabolic HFpEF: mechanisms and therapeutic perspectives.
Cardiac Metabolism in Healthy, Senescent and Diseased States.
Therapeutic targeting of mitochondrial dysfunction in heart failure: a systematic review & meta-analysis of clinical outcomes.
Aerobic exercise reduces lipid accumulation via ACLY-mediated metabolic remodeling to alleviate cardiac remodeling.

Int J Mol Sci. 2026 Jun 26. pii: 5780. [Epub ahead of print]27(13):

Sirtuins at the Interface of Glucose Metabolism, Diabetes, and Heart Failure: Metabolic Sensing in Cardiometabolic Disease.

Jan Krekora, Jarosław Drożdż, Elzbieta Pawlowska, Janusz Blasiak.

  Heart failure (HF) in the setting of diabetes represents a distinct cardiometabolic phenotype characterized by profound disturbances in myocardial glucose metabolism, mitochondrial function, and energetic efficiency. Growing evidence indicates that sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases, play a central role in coordinating glucose utilization, oxidative metabolism, and stress responses in the heart. Findings from genetically modified animal models and cardiomyocyte studies demonstrate that sirtuin impairment, often driven by NAD+ depletion and redox imbalance, further suppresses metabolic activity and promotes metabolic inflexibility, whereas restoration of NAD+ availability or sirtuin activity improves mitochondrial efficiency and metabolic coordination. Human studies, including analyses of myocardial tissue and circulating biomarkers, provide supportive but largely associative evidence, highlighting a substantial translational gap. In this review, we synthesize experimental and clinical data linking sirtuin signaling to the metabolic remodeling observed in diabetic HF, with particular emphasis on glycolysis-oxidation uncoupling, pyruvate dehydrogenase regulation, and mitochondrial dysfunction. We critically discuss context-dependent effects, apparent contradictions, and current limitations of the field, emphasizing differences between diabetic and non-diabetic HF, as well as phenotype- and stage-specific considerations. Finally, we explore therapeutic implications and outstanding questions, positioning the NAD+-sirtuin axis as a unifying mechanistic framework that links systemic metabolic disease to cardiac energetic failure and underscores the potential for metabolism-informed, precision strategies in diabetic HF.

Keywords:  NAD+; diabetes; energetic efficiency; glucose; heart failure; metabolism; mitochondrial impairment; sirtuins

DOI:  https://doi.org/10.3390/ijms27135780
Int J Mol Sci. 2026 Jun 29. pii: 5849. [Epub ahead of print]27(13):

Bioenergetics-Driven Extracellular Vesicle Therapies for Heart Failure: From Preclinical Insights to Regenerative Translation.

Dhienda C Shahannaz, Tadahisa Sugiura.

  Heart failure (HF) is fundamentally a disease of energetic insufficiency, in which impaired mitochondrial efficiency, maladaptive metabolic remodeling, and disrupted intercellular signaling converge at the organ level to limit cardiac performance. Despite advances in pharmacologic and device-based therapies, current treatment paradigms largely modulate hemodynamics or neurohormonal pathways rather than directly restoring myocardial bioenergetic capacity. Emerging evidence positions extracellular vesicles (EVs) as endogenous regulators of cardiac energy homeostasis, capable of orchestrating coordinated metabolic and mitochondrial adaptations across cardiac and non-cardiac cell populations. This review advances a system-level framework in which EVs are conceptualized as bioenergetic therapeutics, i.e., active biological agents that reprogram cellular energy utilization, substrate flexibility, and mitochondrial efficiency, rather than passive carriers of isolated molecular cargo. We synthesize preclinical evidence demonstrating EV-mediated modulation of oxidative phosphorylation, glycolytic balance, redox signaling, and mitochondrial dynamics, and examine how these effects scale from cellular and small-animal models to clinically relevant heart failure phenotypes. Importantly, we highlight organ-level integration, wherein EV signaling interfaces with vascular, immune, and metabolic networks to reshape myocardial energetic demand and supply. By bridging mechanistic insights with translational considerations, this review addresses the central question of how EV-driven bioenergetic reprogramming can be deployed within contemporary HF treatment paradigms. We propose EV-based strategies as complementary or synergistic interventions capable of restoring energetic resilience, reframing heart failure therapy beyond structural repair toward systemic metabolic renewal.

Keywords:  cardiac bioenergetics; energetic insufficiency; extracellular vesicles; heart failure; intercellular energy signaling; metabolic remodeling; mitochondrial efficiency; organ-level metabolism; systems cardiology; translational therapeutics

DOI:  https://doi.org/10.3390/ijms27135849
Int J Mol Sci. 2026 Jun 24. pii: 5716. [Epub ahead of print]27(13):

Circulating β-Hydroxybutyrate in Glycemic Progression and Diabetic Cardiomyopathy: Adaptive Signal or Maladaptive Substrate?

So Ra Kim, Byung-Wan Lee.

  Circulating ketone bodies (KBs), particularly β-hydroxybutyrate (β-HB), have emerged as metabolites with dual roles as both oxidative fuels and metabolic signaling molecules. Beyond serving as an alternative energy substrate, β-HB regulates diverse pathways involved in oxidative stress, inflammation, and mitochondrial function. However, the clinical implications of circulating KBs remain uncertain. This review summarizes current evidence regarding the potential role of KBs in glycemic progression and diabetic cardiomyopathy (DCM). Epidemiologic and experimental studies report conflicting associations between KB levels and the progression to hyperglycemia or type 2 diabetes, with some findings suggesting that elevated KB levels may reflect a metabolically favorable phenotype or a compensatory mechanism, whereas others indicate links to worsening glycemia. Similarly, studies in DCM have produced divergent results, with β-HB reported to improve mitochondrial function and cardiac performance in some models while contributing to metabolic inflexibility and adverse cardiac remodeling in others. We discuss potential mechanisms underlying these discrepancies and propose that the metabolic effects of β-HB are context-dependent, influenced by factors such as circulating concentration, the mode of ketosis induction, and the underlying metabolic or disease stage. Understanding these contextual determinants may help clarify whether β-HB represents an adaptive metabolic signal or a maladaptive substrate shift in cardiometabolic disease.

Keywords:  diabetic cardiomyopathy; glycemic progression; ketone bodies; mitochondrial function; type 2 diabetes; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/ijms27135716
Diabetes Res Clin Pract. 2026 Jul 13. pii: S0168-8227(26)00352-9. [Epub ahead of print]239 113432

Metabolite sensing in cardiometabolic HFpEF: mechanisms and therapeutic perspectives.

Yajie Fan, Xiaoming Wang, Sihan Ai, Shujie Zhang, Yao Zhu, Weimin Jiang.

  Cardiometabolic heart failure with preserved ejection fraction (HFpEF) is a prevalent subtype driven by obesity and diabetes. While systemic inflammation and myocardial fibrosis are known hallmarks, the mechanisms linking metabolic disturbances to cardiac remodeling remain poorly understood. Previous studies have often regarded metabolic abnormalities as passive byproducts of the disease process, neglecting the active regulatory role of metabolites themselves as bioactive signaling molecules. This review elucidates the molecular mechanisms of cardiometabolic HFpEF through the perspective of metabolite sensing. We elaborated on how different cell types decode changes in lipid metabolites, amino acids, TCA cycle intermediates, and gut microbiota-derived signals through specific sensors. These sensing cascades drive adipose tissue dysfunction, immunometabolic abnormalities, impaired myocardial metabolic flexibility, and fibrosis. Additionally, we focused on how intermediate metabolites directly serve as substrates for epigenetic and post-translational modifications, converting transient metabolic stress into a persistent pathological metabolic memory, and briefly discussed sex differences in metabolic sensing. Therapeutically, while SGLT2 inhibitors, GLP-1 receptor agonists, and finerenone provide clinical benefits by restoring metabolic-cardiac homeostasis, targeting upstream metabolite-sensing pathways, such as epigenetic modifier regulators JQ1 and RVX-208 and gut microbiota metabolites, shows great potential. Ultimately, understanding how metabolites are sensed and translated into pathological signals is a key breakthrough for achieving precision therapy in cardiometabolic HFpEF.

Keywords:  Cardiometabolic HFpEF; Epigenetic modifications; Gut microbiota; Immunometabolism; Metabolite sensing; Precision medicine; SGLT2 inhibitors

DOI:  https://doi.org/10.1016/j.diabres.2026.113432
Cells. 2026 Jun 26. pii: 1164. [Epub ahead of print]15(13):

Cardiac Metabolism in Healthy, Senescent and Diseased States.

Uma Bapat, Shahem Albean, Lei Hao, Eun Jung Lee.

  Cardiovascular disease (CVD) is the leading cause of mortality worldwide. The healthy adult heart depends on flexible energy use, but a diseased or injured heart is associated with a loss of flexibility and metabolic remodeling. Since metabolism plays a central role in cardiac health and disease, there is a growing need to understand how metabolic reprogramming contributes to cardiac dysfunction and impaired CM maturation. Human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) are widely used as a platform to study human cardiac development and disease mechanisms. However, current models are limited by metabolic and structural immaturity. This review provides an overview of the dynamic shifts in cardiac metabolic states from fetal development to senescence, while delineating the metabolic signatures of healthy versus disease states. These metabolic switches are orchestrated by a complex interplay of upstream signals driven by variations in substrate availability, post-translational modifications and key transcriptional regulatory networks, which ultimately regulate downstream cardiac remodeling and pathological cascades. As cardiac metabolic function is affected by a coordinated multicellular network, this review also includes the metabolic crosstalk between CMs and non-CMs, including fibroblasts, endothelial cells and immune cells. In addition, various strategies to further mature hiPSC-CMs are summarized to enhance their metabolic profiles. Investigating cardiac metabolic shifts bridges developmental biology, stem cell biology, and regenerative cardiology by revealing how energy metabolism governs cellular identity, maturation, and regenerative potential. These insights are essential for improving stem-cell-derived CMs for disease modeling, drug discovery, and heart repair.

Keywords:  cardiac metabolism; human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs); metabolic maturation; metabolic remodeling; senescence

DOI:  https://doi.org/10.3390/cells15131164
Front Cardiovasc Med. 2026 ;13 1824101

Therapeutic targeting of mitochondrial dysfunction in heart failure: a systematic review & meta-analysis of clinical outcomes.

Omer Mohammed, Shabrin Abdul Rasheed, Ananya Arora, Sharon Velamparambil Sunny, Afthab Salam Kanniyan, Shilla Thomas, Basil Wahid Bhat, Venu Pararath Gopalakrishnan, Jeffrey George, Akiva Rosenzveig, Aravinda Nanjundappa, Shelby Kutty.

   Introduction: Mitochondrial dysfunction is recognised as a key driver of heart failure (HF) pathophysiology, contributing to oxidative stress, apoptosis, and impaired energy production in cardiomyocytes. Although therapeutic agents aimed at restoring mitochondrial function have demonstrated promise in animal models and early-phase clinical trials, their efficacy in clinical practice remains uncertain. This meta-analysis evaluated the impact of these agents on clinical outcomes in HF patients.
Methods: A systematic literature search was conducted across PubMed, Cochrane Library, ScienceDirect, Google Scholar, and ClinicalTrials.gov for studies published through May 2025. Thirty one studies (24 RCTs and 7 crossover trials) were included in meta-analysis. Standardized mean difference was pooled for changes in left ventricular ejection fraction (LVEF), NYHA class and six-minute walk test (6MWT) distance compared to baseline, and risk ratios (RR) were pooled for heart failure-related hospitalisations, and all-cause mortality.
Results: Interventions significantly improved LVEF compared with baseline (SMD: 0.53; 95% CI: 0.42-0.65; p < 0.00001) and control groups (SMD: 0.42; 95% CI: 0.31-0.53). Treatment reduced NYHA functional class (RR: 2.38; 95% CI: 1.48-3.84; p = 0.0004), all-cause mortality (RR: 0.62; 95% CI: 0.47-0.82; p = 0.0007), and HF-related hospitalizations (RR: 0.60; 95% CI: 0.42-0.85; p = 0.004). The certainty of evidence was rated as low across all outcomes owing to substantial heterogeneity and high risk of bias.
Discussion: These findings suggest a potential role for mitochondrial-targeted agents as adjunctive strategies in HF, although the evidence base requires further strengthening through high-quality, adequately powered trials before firm clinical recommendations can be made.
Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251075951, PROSPERO CRD420251075951.

Keywords:  HFpEF; HFrEF; coQ10; elamipretide; heart failure; mitochondrial energetics

DOI:  https://doi.org/10.3389/fcvm.2026.1824101
Life Sci. 2026 Jul 13. pii: S0024-3205(26)00399-1. [Epub ahead of print]402 124590

Aerobic exercise reduces lipid accumulation via ACLY-mediated metabolic remodeling to alleviate cardiac remodeling.

Gaoning Zhang, Zhaoyun Yang, Mingjing Zhang, Dingzheng Zhang, Jing Gao, Longyun Wang, Xufei Zheng, Kai Wang, Ruimeng Chao, Xuejiao Lv, Lijing Zhao, Yanwei Du.

   BACKGROUND: Pathological cardiac remodeling, a key contributor to heart failure, is characterized by significant reprogramming of cardiac energy metabolism. ATP-citrate lyase (ACLY), which connects glucose metabolism with lipid synthesis, plays an important regulatory role in this process. However, the role of ACLY in exercise-induced metabolic remodeling and cardiac remodeling attenuation remains unclear.
METHODS: Cardiac remodeling was induced in H9c2 cells with isoproterenol or urea, or in rats by left anterior descending artery (LAD) ligation or mice by isoproterenol. Interventions included ACLY knockdown, bempedoic acid, or exercise (8/16 wk). Outcomes were assessed via echocardiography, histology, immunohistochemistry, immunofluorescence, and Western blotting.
RESULTS: ACLY was significantly upregulated in cellular and animal models of cardiac remodeling and correlated with cardiomyocyte hypertrophy and lipid accumulation. ACLY knockdown or bempedoic acid treatment attenuated hypertrophy, reduced atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and inhibited lipogenesis. Aerobic exercise was associated with attenuated cardiac remodeling, accompanied by downregulation of ACLY, acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN), and reduced myocardial lipid deposition, with a more pronounced effect observed after 16 weeks than after 8 weeks of training.
CONCLUSION: Aerobic exercise was associated with downregulation of ACLY and reduced myocardial lipogenesis, which may contribute to the attenuation of structural and functional remodeling. This study suggests that the cardioprotective effects of exercise are associated with regulation of lipid metabolism.

Keywords:  ATP-citrate lyase; Aerobic exercise; Cardiac rehabilitation; Cardiac remodeling; Energy metabolism

DOI:  https://doi.org/10.1016/j.lfs.2026.124590