bims-hafaim 2025-05-25 papers

Issue of 2025–05–25
five papers selected by
Kyle McCommis, Saint Louis University

Eur Heart J. 2025 May 21. pii: ehaf324. [Epub ahead of print]

Empagliflozin enhances metabolic efficiency and improves left ventricular hypertrophy in a hypertrophic cardiomyopathy mouse model.

BACKGROUND AND AIMS: Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and impaired metabolic efficiency. This study investigates the therapeutic potential of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin (EMPA) in ameliorating these pathological features in a mouse model carrying the myosin R403Q mutation.
METHODS: Male mice harbouring the R403Q mutation were treated with EMPA for 16 weeks. Multi-nuclear magnetic resonance spectroscopy (31P, 13C, and 23Na MRS), echocardiography, transcriptomic, proteomic, and phosphoproteomic profiling were utilized to assess metabolic, structural, and functional changes.
RESULTS: Empagliflozin facilitated the coupling of glycolysis with glucose oxidation and normalized elevated intracellular sodium levels. Treatment resulted in a significant reduction in LVH and myocardial fibrosis as evidenced by echocardiography and histopathology. These structural improvements correlated with enhancements in mitochondrial adenosine triphosphate (ATP) synthesis, fatty acid oxidation, and branched-chain amino acid catabolism. Furthermore, EMPA improved left ventricular diastolic function and contractile reserve, underscored by improved ATP production and reduced energy cost of contraction. Notably, these benefits were linked to down-regulation of the mammalian target of rapamycin signalling pathway and normalization of myocardial substrate metabolic fluxes.
CONCLUSIONS: Empagliflozin significantly mitigates structural and metabolic dysfunctions in a mouse model of HCM, underscoring its potential as a therapeutic agent for managing this condition. These findings suggest broader applicability of SGLT2i in cardiovascular diseases, including those due to myocardial-specific mutations, warranting further clinical investigation.

Keywords: Branched-chain amino acids; Cardiac energetics; Cardiac metabolism; Hypertrophic cardiomyopathy; Metabolic reprogramming; SGLT2 inhibition; Uncoupled glycolysis; mTOR

DOI: https://doi.org/10.1093/eurheartj/ehaf324

Fitoterapia. 2025 May 19. pii: S0367-326X(25)00258-8. [Epub ahead of print]184 106633

Prophylactic administration of Kanli granule maintains fatty acid oxidation in the myocardium to prevent heart failure via activating AMPK/PPARα/CPT1A pathway: A network pharmacology-based study.

Zhejun Zhao, Yuanlong Sun, Meijun Jia, Meixian Jiang, Xiaofen Ruan.

BACKGROUND: Abnormal energy metabolism plays a crucial role in the pathogenesis of heart failure (HF). Kanli granule (KLG), as an effective herbal medicine for treating HF, has been used in clinical practice for nearly 30 years. However, its underlying mechanisms have not been fully elucidated.
METHODS: This study combined network pharmacology, molecular docking, and in vivo experiments to explore KLG's effect on HF. Wistar rats with AAC-induced HF were orally administered KLG (0.675/1.35/2.7 g/kg) for 32 weeks. Assessments included heart weight index, echocardiography, histopathology, fatty acid metabolism (FAM) targets, and myocardial energy metrics. We focused on fatty acid oxidation (FAO) pathway, measuring AMPK, PPARα, and CPT1A at protein and gene levels.
RESULTS: KLG maintained cardiac function in AAC rats. Network pharmacology identified PPAR and AMPK pathways as key in FAM. Molecular docking showed strong affinity of KLG components to FAO targets PPARα and CPT1A. KLG significantly enhanced myocardial energy metabolism, reduced myocardial FFA levels, and increased ATP/ADP ratios. It activated AMPK and upregulated FAO-related genes, including PPARα and CPT1A.
CONCLUSION: KLG improves FAO in AAC-induced HF rats by activating the AMPK/PPARα/CPT1A pathway, reducing myocardial FFA levels, and improving myocardial microstructure and cardiac function.

Keywords: Abdominal aortic constriction; Fatty acid oxidation; Heart failure; Kanli granule; Molecular docking; Network pharmacology

DOI: https://doi.org/10.1016/j.fitote.2025.106633

Heart Fail Rev. 2025 May 21.

The effect of GLP-1 receptor agonists on cardiac remodeling in heart failure patients with preserved and reduced ejection fraction: a systematic review and meta-analysis.

Hasan Fareed Siddiqui, Saad Ahmed Waqas, Ruqiat Masooma Batool, Hussain Salim, Abdul Mannan Khan Minhas, Syed Farhan Hasni, Amro Alsaid, Anna Sannino, Aasim M Afzal, Muhammad Shahzeb Khan.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) have shown promising effects on heart failure (HF) outcomes, particularly in phenotype-specific populations. However, their impact on cardiac structure and function in HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) remains unclear.
METHODS: Medline, Cochrane Library, and Scopus were queried through December 2024 for primary and secondary analyses of randomized controlled trials comparing GLP-1RA with placebo in HF patients. Outcomes included changes in left ventricular ejection fraction (LVEF), end-diastolic volume (LVEDV), end-systolic volume (LVESV), global longitudinal strain (GLS), left ventricular mass, left atrial volume (LAV), and NT-proBNP levels. Random-effects models were used to calculate weighted mean differences (WMDs) or hazard ratios (HRs).
RESULTS: Six trials (n = 1,195) were included, with three each evaluating HFpEF and HFrEF populations. In patients with HFpEF, GLP-1RA significantly reduced the LV mass (WMD: -8.6 g; 95% CI: -14.6, -2.6; p = 0.005) and LAV (WMD: -5.4 ml; 95% CI: -8.8, -2.0; p = 0.002) and lowered NT-proBNP concentration throughout (HR: 0.85; 95% CI: 0.8, 0.9; p < 0.001). A decrease in LAV was observed in the HFrEF population (WMD: -5.4 ml [95% CI: -8.8, -2.0]; p = 0.002). However, no significant improvements were observed in LVEF, LVEDV, LVESV, or GLS. There were significant differences between HFpEF and HFrEF for LVEDV (p = 0.01) and LVESV (p = 0.04).
CONCLUSIONS: GLP-1RA demonstrated phenotype-specific benefits, improving structural remodeling in HFpEF but showing limited effects in HFrEF. These findings highlight the importance of targeted therapeutic strategies based on HF phenotypes. Further research is warranted to elucidate underlying mechanisms and optimize patient selection.

Keywords: Cardiac remodeling; GLP-1 receptor agaonists; HFpEF; HFrEF; Heart failure

DOI: https://doi.org/10.1007/s10741-025-10523-0

Circ Res. 2025 May 23. 136(11): 1382-1406

Gut-Heart Axis: The Role of Gut Microbiota and Metabolites in Heart Failure.

Matthew Snelson, Rikeish R Muralitharan, Chia-Feng Liu, Lajos Markó, Sofia K Forslund, Francine Z Marques, W H Wilson Tang.

Heart failure is a global health issue with significant mortality and morbidity. There is increasing evidence that alterations in the gastrointestinal microbiome, gut epithelial permeability, and gastrointestinal disorders contribute to heart failure progression through various pathways, including systemic inflammation, metabolic dysregulation, and modulation of cardiac function. Moreover, several medications used to treat heart failure directly impact the microbiome. The relationship between the gastrointestinal tract and the heart is bidirectional, termed the gut-heart axis. It is increasingly understood that diet-derived microbial metabolites are key mechanistic drivers of the gut-heart axis. This includes, for example, trimethylamine N-oxide and short-chain fatty acids. This review discusses current insights into the interplay between heart failure, its associated risk factors, and the gut microbiome, focusing on key metabolic pathways, the role of dietary interventions, and the potential for gut-targeted therapies. Understanding these complex interactions could pave the way for novel strategies to mitigate heart failure progression and improve patient outcomes.

Keywords: butyrates; gastrointestinal microbiome; heart failure; inflammation; intestinal barrier function; microbiota

DOI: https://doi.org/10.1161/CIRCRESAHA.125.325516

Autophagy Rep. 2024 ;3(1): 2405331

Methods for detection of cardiac glycogen-autophagy.

Parisa Koutsifeli, Lorna J Daniels, Joshua Neale, Sarah Fong, Upasna Varma, Marco Annandale, Xun Li, Yohanes Nursalim, James R Bell, Kate L Weeks, Aleksandr Stotland, David J Taylor, Roberta A Gottlieb, Lea M D Delbridge, Kimberley M Mellor.

Glycogen-autophagy ('glycophagy') is a selective autophagy process involved in delivering glycogen to the lysosome for bulk degradation. Glycophagy protein intermediaries include STBD1 as a glycogen tagging receptor, delivering the glycogen cargo into the forming phagosome by partnering with the Atg8 homolog, GABARAPL1. Glycophagy is emerging as a key process of energy metabolism and development of reliable tools for assessment of glycophagy activity is an important priority. Here we show that antibodies raised against the N-terminus of the GABARAPL1 protein (but not the full-length protein) detected a specific endogenous GABARAPL1 immunoblot band at 18kDa. A stable GFP-GABARAPL1 cardiac cell line was used to quantify GABARAPL1 lysosomal flux via measurement of GFP puncta in response to lysosomal inhibition with bafilomycin. Endogenous glycophagy flux was quantified in primary rat ventricular myocytes by the extent of glycogen accumulation with bafilomycin combined with chloroquine treatment (no effect observed with bafilomycin or chloroquine alone). In wild-type isolated mouse hearts, bafilomycin alone and bafilomycin combined with chloroquine (but not chloroquine alone) elicited a significant increase in glycogen content signifying basal glycophagy flux. Collectively, these methodologies provide a comprehensive toolbox for tracking cardiac glycophagy activity to advance research into the role of glycophagy in health and disease.

Keywords: Atg8; GABARAPL1; autophagy; glycogen; glycophagy flux

DOI: https://doi.org/10.1080/27694127.2024.2405331