bims-hafaim 2025-09-14 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–09–14
eight papers selected by
Kyle McCommis, Saint Louis University

Fumarate hydratase ameliorates pressure overload induced cardiac remodeling by controlling Elovl7-mediated biosynthesis of unsaturated fatty acids.
Metabolic-epigenetic interactions in heart failure: Current understanding and future directions.
Metabolomics Insights into the Benefits of SGLT2 Inhibitors in Type 2 Diabetes.
Silybin Mitigates Post-Myocardial Infarction Heart Failure in Mice via Modulation of HIF-1α-Driven Glycolysis and Energy Metabolism.
Advances in the therapeutic applications of dichloroacetate as a metabolic regulator: A review.
Cardiometabolic and renal benefits of sodium-glucose cotransporter 2 inhibitors.
Cardiac sodium-glucose co-transporter 1 (SGLT1) contributes to heart failure in a mouse model of diabetic cardiomyopathy.
Circulating metabolites in patients with chronic heart failure are not related to gut leakage or gut dysbiosis.

Acta Pharmacol Sin. 2025 Sep 12.

Fumarate hydratase ameliorates pressure overload induced cardiac remodeling by controlling Elovl7-mediated biosynthesis of unsaturated fatty acids.

Lan-Lan Li, Chao-Jun Sun, Xiao-Tong Mo, Yun Xing, Tong Zhang, Heng Zhang, Nan Zhao, Xiao-Feng Zeng, Sha-Sha Wang, Yan-Yan Meng, Sai-Yang Xie, Wei Deng.

  Pathological cardiac hypertrophy as a major contributor to heart failure is characterized by complicated mechanisms. Fumarate hydratase (FH) is a crucial enzyme in the tricarboxylic acid cycle. FH mutations and dysfunction have been implicated in various pathological processes including hereditary leiomyomatosis and renal cell cancer, neurodegenerative diseases, metabolic syndrome and cardiovascular diseases. In this study we investigated the role of FH in cardiac hypertrophy. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery as well as in neonatal rat cardiomyocytes (NRCMs) by phenylephrine (PE) stimulation. We showed that the expression levels of FH were gradually increased with development of cardiac hypertrophy in TAC mice. Cardiomyocyte-specific overexpression of FH by intravenous injection of recombinant adeno-associated virus serotype 9 (AAV9) carrying FH two weeks before TAC surgery prevented the morphological changes, cardiac dysfunction and remodeling in TAC mice; FH overexpression also significantly attenuated PE-induced hypertrophy in NRCMs along with suppressed expression of hypertrophic markers ANP, BNP and β-MHC. We demonstrated that FH overexpression alleviated TAC-induced mitochondrial structural damage in cardiomyocytes and facilitated metabolic remodeling. RNA sequencing and untargeted metabolomics revealed that FH overexpression mitigated myocardial remodeling and mitochondrial metabolism dysfunction in TAC mice mainly by suppressing the transcription factor SREBP and reducing the gene expression of elongation of very long chain fatty acids protein 7 (Elovl7). Overexpression of Elovl7 reversed the protective effects of FH in both TAC mice and PE-stimulated NRCMs. Knockdown of the transcription factor SREBP reduced Elovl7 expression, thereby exerting cardioprotective effects. In conclusion, we demonstrate that FH overexpression prevents cardiac hypertrophy in mice by regulating glucose and lipid metabolism through the malate-SREBP-Elovl7 pathway.

Keywords:  Elovl7; SREBP; cardiac hypertrophy; fumarate hydratase; lipid metabolism; myocardial remodeling

DOI:  https://doi.org/10.1038/s41401-025-01637-0
Biochem Biophys Res Commun. 2025 Sep 06. pii: S0006-291X(25)01324-5. [Epub ahead of print]783 152608

Metabolic-epigenetic interactions in heart failure: Current understanding and future directions.

Benjamin Flowers, Bea Duric.

  Heart failure remains a major global health concern characterized by complex pathophysiological processes and significant clinical challenges. While the distinct roles of metabolic and epigenetic dysregulation in heart failure are increasingly recognized, their intricate interplay remains a critical, yet underexplored, aspect of its pathophysiology. This review provides a comprehensive examination of this metabolic-epigenetic crosstalk, exploring how metabolic changes, such as impaired fatty acid oxidation, increased glycolysis, and mitochondrial dysfunction, alter epigenetic landscapes through shifts in intermediary metabolites including acetyl-CoA, NAD+, and α-ketoglutarate. Conversely, epigenetic dysregulation in the forms of DNA methylation and histone acetylation, for example, contribute to metabolic maladaptation through suppression of critical genes for oxidative phosphorylation and mitochondrial biogenesis. By providing an integrative framework linking metabolic and epigenetic circuits, this review aims to enhance our understanding of this pervasive condition and highlight emerging therapeutic targets within these networks.

Keywords:  Epigenetic changes; Glycolysis; Heart failure; Histone modifications; Metabolism; Warburg effect

DOI:  https://doi.org/10.1016/j.bbrc.2025.152608
Clin Pharmacol. 2025 ;17 253-267

Metabolomics Insights into the Benefits of SGLT2 Inhibitors in Type 2 Diabetes.

Artemis Kyriakidou, Theocharis Koufakis, Helen Gika, Kalliopi Kotsa.

   Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an established class of agents in the treatment of type 2 diabetes mellitus (T2DM), with proven cardiovascular and renal benefits. However, their precise mechanisms of action remain incompletely understood. Metabolomics offers a powerful approach to uncovering drug-induced alterations in metabolic pathways.
Aim: This narrative review summarizes the available human evidence on the metabolomic effects of SGLT2 inhibitors, with a focus on their potential implications for metabolic adaptation and cardiorenal protection.
Methods: We performed a comprehensive literature search of human studies that applied metabolomic analyses to evaluate the effects of SGLT2 inhibitors in T2DM. Both targeted and untargeted metabolomic approaches were considered.
Results: Across studies, SGLT2 inhibitors consistently induce a metabolic shift away from glucose utilization toward more energy-efficient substrates. Key metabolite changes include increases in ketone bodies, alterations in branched-chain amino acids, and modulation of intermediates of the tricarboxylic acid cycle.
Conclusion: SGLT2 inhibitors consistently induce a metabolic shift away from glucose utilization toward more energy-efficient substrates, including ketone bodies, fatty acids, and certain amino acids. These metabolomic adaptations may underlie their observed cardiovascular and renal protective effects. While these findings support the "thrifty fuel" hypothesis, additional longitudinal studies with standardized methodologies and precision medicine approaches are needed to fully define the clinical significance of these metabolic adaptations.

Keywords:  SGLT-2 inhibitors; metabolomics; type 2 diabetes mellitus

DOI:  https://doi.org/10.2147/CPAA.S497906
Nutrients. 2025 Aug 28. pii: 2800. [Epub ahead of print]17(17):

Silybin Mitigates Post-Myocardial Infarction Heart Failure in Mice via Modulation of HIF-1α-Driven Glycolysis and Energy Metabolism.

Mengyuan Wang, Jinhong Chen, Zhongzheng Zhang, Tianyu Wang, Jiaqi Zhao, Xiao Wang, Junyan Wang, Haowen Zhuang.

   BACKGROUND: Post-myocardial infarction (MI) heart failure (HF) is characterized by myocardial energy metabolism disorder, with excessive glycolysis playing a key role in its progression. Silybin (SIL), a flavonoid derived from Silybum marianum, has demonstrated hepatoprotective and metabolic regulatory effects. However, the role of this flavonoid in ameliorating post-myocardial infarction heart failure (post-MI HF) by modulating energy metabolism remains unclear.
METHODS: This study employed an oxygen-glucose deprivation (OGD) model to induce myocardial cell injury in vitro, with YC-1 treatment used to inhibit hypoxia-inducible factor-1α (HIF-1α) for mechanistic validation. A myocardial infarction-induced HF mouse model was used for in vivo experiments.
RESULTS: In vitro, SIL enhanced cell viability, increased ATP levels, and decreased lactate production and reactive oxygen species (ROS) accumulation in OGD-treated myocardial cells. SIL downregulated the mRNA and protein expression of HIF-1α, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA) while inhibiting HIF-1α nuclear translocation. Furthermore, SIL suppressed glycolytic proteins (PFKFB3, GLUT1, and LDHA) in a manner comparable to the HIF-1α inhibitor YC-1. This confirms that SIL's inhibition of glycolysis is HIF-1α-dependent. In vivo, SIL treatment improved cardiac function parameters (LVEF and LVFS) and attenuated left ventricular remodeling (LVID;d and LVID;s) in post-MI HF mice. Additionally, myocardial fibrosis markers were significantly reduced, accompanied by a decrease in the myocardial mRNA and protein expression of glycolytic proteins, including HIF-1α, PFKFB3, GLUT1, and LDHA.
CONCLUSIONS: Silybin effectively ameliorates post-myocardial infarction heart failure through the HIF-1α-mediated regulation of glycolysis, leading to improved myocardial energy metabolism and enhanced cardiac function.

Keywords:  HIF-1α; energy metabolism disorder; glycolysis; heart failure; silybin

DOI:  https://doi.org/10.3390/nu17172800
Medicine (Baltimore). 2025 Sep 05. 104(36): e44295

Advances in the therapeutic applications of dichloroacetate as a metabolic regulator: A review.

Xiaohuan Wu, Min Shang, Meichuan Li, Yujuan Liu, Han Hu, Ping Zhang, Qiuyi He, Shide Lin.

  Dichloroacetate (DCA), as a pan-inhibitor of pyruvate dehydrogenase kinase, plays a crucial role in energy metabolism and mitochondrial function. DCA decreases lactic acid synthesis, enhances mitochondrial oxidative phosphorylation, and regulates aerobic glycolysis. During the last decade, more and more studies have found that disorders of energy metabolism and mitochondrial dysfunction play a pivotal role in the development and progression of various diseases, and the role of DCA in cancer, metabolic diseases, and inflammatory diseases has been extensively explored in both basic and clinical studies. In this review, we summarize advances in the therapeutic applications of DCA as a metabolic regulator.

Keywords:  adverse effect; dichloroacetate; glycolysis; mitochondria; therapeutic applications

DOI:  https://doi.org/10.1097/MD.0000000000044295
Nat Rev Endocrinol. 2025 Sep 11.

Cardiometabolic and renal benefits of sodium-glucose cotransporter 2 inhibitors.

Yong-Ho Lee, Soo Lim, Melanie J Davies.

The therapeutic scope of sodium-glucose cotransporter 2 (SGLT2) inhibitors has expanded beyond glycaemic regulation in the management of diabetes mellitus. Studies published in the past few years highlight their substantial effect on cardiovascular outcomes, notably in decreasing mortality and the need for heart failure-related hospitalization. These agents also lead to pronounced improvements in a range of renal outcomes. The primary actions of SGLT2 inhibition, glycosuria and natriuresis, are pivotal in enhancing glucose control, promoting weight loss and lowering blood pressure. These effects initiate a series of beneficial mechanisms: facilitating haemodynamic improvement by reducing interstitial volume, enhancing cardiac function, boosting energy efficiency through altered ketone body metabolism and mitigating inflammation and oxidative stress. Additional effects include heightened erythropoiesis, reduced hyperuricaemia and increased levels of angiotensin-converting enzyme 2 and angiotensin (1-7). SGLT2 inhibitors also attenuate sympathetic overactivity by modulating neurohumoral activation and renal afferent signalling, contributing to their cardioprotective and renoprotective profiles. This Review provides a comprehensive overview of the diverse mechanisms underpinning the cardiometabolic and renal effects of SGLT2 inhibitors, emphasizing their clinical relevance and therapeutic potential.

DOI: https://doi.org/10.1038/s41574-025-01170-4
Basic Res Cardiol. 2025 Sep 11.

Cardiac sodium-glucose co-transporter 1 (SGLT1) contributes to heart failure in a mouse model of diabetic cardiomyopathy.

Zhao Li, Sydney Freiberg, Meredith L Music, Lina Gu, Sarah Nacos, Joseph P Phillips, Adil Hassan, Kamel Shibbani, Sanah S Munir, Vooha K Kumar, Luke Halligan, Mia E Michel, Benjamin F London, Ngan Bui, Michael Cicha, Valerie Buffard, E Dale Abel, Ferhaan Ahmad.

  Diabetes mellitus can lead to a cardiomyopathy independent of other risk factors such as coronary artery disease and hypertension, in up to 75% of patients. The prevalence of diabetic cardiomyopathy in the population is 1.1%. We previously showed that SGLT1 is expressed in cardiomyocytes and is further upregulated in diabetic cardiomyopathy and other forms of heart failure. In this study, we sought to determine the mechanisms by which cardiac SGLT1 contributes to the pathophysiology of heart failure in diabetes, obesity, and insulin resistance. We determined whether transgenic mice with cardiomyocyte-specific knockdown of SGLT1 (TGSGLT1-DOWN) had attenuation of cardiomyopathy after induction of obesity and insulin resistance by exposure to a high fat diet (HFD) from ages 8-28 weeks. TGSGLT1-DOWN mice and wildtype (WT) littermates exhibited similar increases in body weight and blood glucose after exposure to HFD. Nevertheless, TGSGLT1-DOWN mice exhibited attenuation of cardiomyopathy, manifested by less hypertrophy, systolic and diastolic dysfunction, fibrosis, nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2) activation, and reactive oxygen species (ROS) production. In vivo hyperinsulinemia and in vitro exposure of cardiomyocytes to high glucose or insulin led to an increase in SGLT1 expression by increasing binding of the transcription factors HNF-1 and Sp1 to the SGLT1 gene (Slc5a1), and the transcript stabilizer HuR to SGLT1 mRNA. SGLT1 may contribute to cardiac injury in obesity and insulin resistance by stimulating ROS through its interaction with EGFR. SGLT1 may represent a therapeutic target for inhibition to prevent or to reverse diabetic cardiomyopathy.

Keywords:  Cardiomyopathy; Diabetes; Fibrosis; Glucose; Insulin; Oxidative stress

DOI:  https://doi.org/10.1007/s00395-025-01136-7
PLoS One. 2025 ;20(9): e0331692

Circulating metabolites in patients with chronic heart failure are not related to gut leakage or gut dysbiosis.

Andraž Nendl, Sajan C Raju, Peder R Braadland, Anna Nordborg, Vibeke Bratseth, Kaspar Broch, Silje F Jørgensen, Pål Aukrust, Karsten Kristiansen, Johannes R Hov, Marius Trøseid, Ayodeji Awoyemi.

BACKGROUND: The gut microbiota produces numerous metabolites that can enter the circulation and exert effects outside the gut. Several studies have reported altered gut microbiota composition and circulating metabolites in patients with chronic heart failure (HF) compared to healthy controls. Limited data is available on the interplay between dysbiotic features of the gut microbiota and altered circulating metabolites in HF patients. We aimed to examine differences in circulating metabolites between people with and without chronic HF, and their association with gut microbiota dysbiosis and cardiac function.
METHODS: We collected plasma, serum, and stool samples from 123 adult patients with stable chronic HF and left ventricular ejection fraction (LVEF) ≤40%, and healthy controls (plasma: n = 51, stool samples: n = 69). Metabolomic and lipidomic profiling of plasma was performed using liquid chromatography with tandem mass spectrometry. Principal component analysis was used to explore differences in circulating profiles. Over-representation analysis was performed to identify pathways in which relevant metabolites were involved. Stool samples were sequenced using shotgun metagenomics. We calculated a dysbiosis index based on differential abundances of microbial taxa in patients vs. controls.
RESULTS: After adjusting for age, sex, and sampling location, we identified 67 enriched metabolites and 24 enriched lipids, and 115 depleted metabolites and 6 depleted lipids in HF patients compared to healthy controls. LVEF, N-terminal pro B-type natriuretic peptide, gut leakage markers, dysbiosis index, and fiber intake were not significantly related to any of the differentially abundant metabolites or lipids. Pathways related to energy metabolism differed most between HF patients and controls, however medication adjustment abolished all differences in circulating profiles.
CONCLUSIONS: Patients with chronic HF had distinct metabolomic and lipidomic profiles and energy metabolism differed significantly compared to healthy controls before adjusting for medication use. However, the alterations were not related to gut dysbiosis, gut leakage markers, cardiac function, or fiber intake.

DOI: https://doi.org/10.1371/journal.pone.0331692