bims-hafaim 2025-10-12 papers

Issue of 2025–10–12
five papers selected by
Kyle McCommis, Saint Louis University

Curr Treat Options Cardiovasc Med. 2025 ;27(1): 65

Metabolic Reprogramming in Heart Failure: From Energy Starvation to Therapeutic Targets.

Mariam Meddeb, Joseph R Goldenberg, Sydney C Jenkin, Virginia S Hahn.

Purpose of Review: The goals of this review are to summarize the current literature regarding metabolic abnormalities in heart failure and propose therapies that can induce metabolic reprogramming to benefit the diseased heart.
Recent Findings: Analysis of cardiac and skeletal muscle metabolism in heart failure has revealed several abnormalities including lower PCr/ATP ratio (indicating diminished myocardial energy reserves), altered substrate utilization, and mitochondrial abnormalities. Several advances in both non-invasive and invasive methods to studying cardiac metabolism have allowed recent key contributions to the field. Promising therapeutic strategies include shifting towards increased utilization of ketones and fatty acids, targeting mitochondrial biogenesis and function, and activation of genes that promote metabolic remodeling. Several current therapies lead to metabolic reprogramming, including both drug and device-based therapies such as cardiac resynchronization therapy (CRT) and left ventricular assist devices (LVADs).
Summary: Strategies to induce metabolic reprogramming in the diseased heart need further study. Future research should address differences in metabolic abnormalities in HFrEF and HFpEF, methods to study metabolic responses to therapies, and impact of metabolic reprogramming on clinical outcomes in heart failure.

Keywords: Heart failure; Heart failure therapeutics; Metabolic reprogramming; Metabolism

DOI: https://doi.org/10.1007/s11936-025-01121-2

Nat Commun. 2025 Oct 10. 16(1): 9022

Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.

Fan Yu, Jingsi Duan, Zhengyin Lou, Guo-Ping Shi, Fuzhe Gong, Lingfeng Zhong, Derong Chen, Li Xu, Tingting Hong, Xinyang Hu, Jinghai Chen, Jian'an Wang, Deling Yin.

Myocardial energy metabolism disorders are essential pathophysiology in sepsis-associated myocardial injury. Yet, the underlying mechanisms involving impaired mitochondrial respiratory function upon myocardial injury remain poorly understood. Here we identify an unannotated and cardiomyocyte-enriched long non-coding RNA, Cpat (cardiac-protector-associated transcript), that plays an important role in regulating the dynamics of cardiomyocyte mitochondrial tricarboxylic acid (TCA) cycle. Cpat is essential to the mitochondrial respiratory function by targeting key metabolic enzymes and modulating TCA cycle flux. Specifically, Cpat enhances the association of TCA cycle core components malate dehydrogenase (MDH2), citrate synthase (CS), and aconitase (ACO2). Acetyltransferase general control non-repressed protein-5 (GCN5) acetylates CS and destabilizes the MDH2-CS-ACO2 complex formation. Cpat inhibits this GCN5 activity and facilitates MDH2-CS-ACO2 complex formation and TCA cycle flux. We reveal that Cpat-mediated mitochondrial metabolic homeostasis is vital in mitigating myocardial injury in sepsis-induced cardiomyopathy, positioning Cpat as a promising therapeutic target for preserving myocardial cellular metabolism and function.

DOI: https://doi.org/10.1038/s41467-025-64072-z

Front Cardiovasc Med. 2025 ;12 1647747

From bench to bedside: investigating SGLT2 inhibitors as a novel strategy against chemotherapy-induced cardiomyopathy.

Rade Jibawi Rivera, Faris Muaref, Sulaiman Paika, Abdullah Ruyyashi, Christopher S Gondi.

Background: Anthracyclines are essential components of chemotherapeutic regimens for a broad spectrum of malignancies, yet their utility is constrained by cumulative, dose-dependent cardiotoxicity, often culminating in non-ischemic cardiomyopathy and heart failure. The pathogenesis involves oxidative stress, mitochondrial dysfunction, and topoisomerase IIβ-mediated DNA damage in cardiomyocytes. While ACE inhibitors and angiotensin receptor blockers (ARBs) have demonstrated modest cardioprotective effects, the efficacy of newer heart failure therapies remains underexplored. Sodium-glucose co-transporter-2 (SGLT2) inhibitors, endorsed as Class I therapy for heart failure with reduced ejection fraction (HFrEF) per 2022 AHA/ACC/HFSA guidelines, have shown robust cardioprotective effects in large cardiovascular outcomes trials. However, their potential to prevent or attenuate anthracycline-induced cardiotoxicity has not been systematically evaluated. This study aimed to assess preclinical and clinical evidence supporting their use in anthracycline-exposed populations.
Methods: A systematic review was conducted by PRISMA 2020 guidelines. Comprehensive searches of major medical databases and clinical trial registries were performed through March 2025. Eligible studies investigated SGLT2 inhibitors, β-blockers, or ACE inhibitors in adult patients receiving anthracycline-based chemotherapy or in animal models replicating this exposure. Primary outcomes included changes in LVEF, GLS, and incidence of heart failure. Studies involving pre-existing heart failure or non-anthracycline-related cardiotoxicity were excluded.
Results: Preclinical studies (n = 4) consistently demonstrated that SGLT2 inhibitors mitigated cardiomyocyte injury, fibrosis, and oxidative stress, preserving cardiac function in anthracycline-exposed models. In one study, LVEF was significantly higher in animals treated with SGLT2 inhibitors (61.3% ± 11%) vs. controls (49.2% ± 8%, p = 0.007). Additional studies corroborated reduced histopathological damage and improved myocardial performance. No clinical trials to date have specifically assessed SGLT2 inhibitors in oncology populations. Nevertheless, major cardiovascular trials (e.g., EMPA-REG OUTCOME, DECLARE-TIMI 58) have demonstrated substantial reductions in heart failure events among non-cancer cohorts. In contrast, ACE inhibitors and β-blockers have shown variable efficacy during chemotherapy, with inconsistent findings across studies.
Conclusions: SGLT2 inhibitors exhibit consistent cardioprotective effects in preclinical models of anthracycline cardiotoxicity and possess well-established efficacy in broader cardiovascular populations. These findings underscore the critical need for prospective trials evaluating their safety and therapeutic potential in cardio-oncology, with implications for reshaping current preventive strategies.
Systematic Review Registration: PROSPERO [1056661].

Keywords: ACE-inhibitors; SGLT2 inhibitors; anthracyclines; cardioprotection; cardiotoxicity; heart failure prevention; β-blockers; β-blockers cardiotoxicity

DOI: https://doi.org/10.3389/fcvm.2025.1647747

JACC Heart Fail. 2025 Oct 03. pii: S2213-1779(25)00588-8. [Epub ahead of print]13(11): 102660

Semaglutide and Exercise Function in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program.

STEP-HFpEF Trial Committees and Investigators

BACKGROUND: Exercise function quantified by 6-minute walk distance (6MWD) is severely impaired in patients with heart failure with preserved ejection fraction (HFpEF).
OBJECTIVES: This prespecified secondary analysis of pooled data from the STEP-HFpEF Program (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) examined factors associated with impaired exercise function at baseline, detailed effects of semaglutide on 6MWD, and on other key trial endpoints according to baseline 6MWD in patients with HFpEF.
METHODS: Associates of 6MWD were assessed at baseline, and effects of semaglutide on 6MWD were evaluated at early (20 weeks) and final (52 weeks) time points, across subgroups, and according to the magnitude of weight loss achieved. Effects of semaglutide on the dual primary (changes in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score [KCCQ-CSS] and body weight) and secondary/exploratory endpoints were contrasted by tertiles of baseline 6MWD.
RESULTS: The authors randomized 1,145 patients to semaglutide or placebo. Compared with patients who had obesity-related HFpEF and higher 6MWD, those with lower 6MWD were older and had lower KCCQ-CSS, higher body mass index and waist circumference, greater systemic inflammation (higher C-reactive protein), and more severe congestion (higher N-terminal pro-B-type natriuretic peptide, more diuretic use). Treatment with semaglutide increased 6MWD compared with placebo, an effect apparent at 20 weeks (treatment difference 14.6 m [95% CI: 8.6-20.7 m; P < 0.0001]) that was maintained at 52 weeks (treatment difference 17.1 m [95% CI: 9.2-25.0 m; P < 0.0001]). Increases in 6MWD with semaglutide (vs placebo) were similar across all relevant subgroups, with no significant interactions. Treatment with semaglutide increased KCCQ-CSS and reduced body weight, reduced C-reactive protein, improved the hierarchical composite (death, heart failure events, change in KCCQ-CSS and 6MWD), and reduced N-terminal pro-B-type natriuretic peptide across the spectrum of baseline 6MWD (all Pinteraction = NS). Each 1-unit decrease in body mass index on treatment with semaglutide was associated with a 4.1 m (95% CI: 2.4-5.7 m) increase in 6MWD (P < 0.0001).
CONCLUSIONS: In patients with obesity-related HFpEF, impaired 6MWD is most strongly associated with excess adiposity, congestion, and inflammation. Semaglutide-mediated improvements in HF-related symptoms, physical limitations, and exercise function were consistent across the spectrum of baseline 6MWD, observed as early as 20 weeks after the initiation of treatment, preceding maximal weight loss. The effects were consistent across subgroups. There was strong correlation between greater magnitude of weight loss and greater improvements in 6MWD. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF], NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM], NCT04916470).

Keywords: 6-minute walk distance; heart failure with preserved ejection fraction; obesity; semaglutide

DOI: https://doi.org/10.1016/j.jchf.2025.102660

Cureus. 2025 Sep;17(9): e91710

Reviving the Mitochondria: A Hopeful Horizon in Refractory Heart Failure.

Zeeshan Ahmed, Fnu Abdul Rehman, Syed Faqeer Hussain Bokhari.

Refractory heart failure (HF) remains a pressing clinical challenge despite substantial progress in pharmacologic and device-based interventions. While current therapies target neurohormonal, hemodynamic, and metabolic derangements, a crucial element of cellular dysfunction often remains overlooked: mitochondrial health. Mitochondrial dysfunction plays a central role in the pathogenesis and progression of HF, contributing to bioenergetic failure, oxidative stress, and cardiomyocyte death. Recent advances in mitochondrial-targeted therapies have opened new possibilities for treating HF at its energetic roots. This editorial explores the pathophysiological role of mitochondria in HF, reviews emerging therapeutic strategies aimed at restoring mitochondrial function, and outlines key challenges that must be addressed to translate these innovations into clinical practice.

Keywords: elamipretide; heart failure; mitochondira; mitoq; perhexiline; pgc-1α; trimetazidine; urolithin

DOI: https://doi.org/10.7759/cureus.91710