bims-hafaim 2025-09-28 papers

Issue of 2025–09–28
seven papers selected by
Kyle McCommis, Saint Louis University

Res Sq. 2025 Sep 17. pii: rs.3.rs-7556256. [Epub ahead of print]

Succinate-GPR91 signaling promotes cardiomyocyte metabolic reprogramming and NAD⁺ production to alleviate HFpEF.

YuMeng Jia, WenHui Niu, Lu Liu, Qun Zhang, DingWei Li, TangYu Dai, Jurgen Wess, Lei Wang, Jie Du.

Background: Disrupted cardiomyocyte energy metabolism is a hallmark of heart failure with preserved ejection fraction (HFpEF). Succinate, a key intermediate of the tricarboxylic acid cycle, is markedly decreased in HFpEF myocardium. Beyond its metabolic role, succinate functions as a signaling molecule that activates GPR91 to regulate metabolic and immune pathways. However, the precise contributions and mechanisms of cardiomyocyte succinate-GPR91 signaling in HFpEF pathogenesis remain largely unknown. Methods: HFpEF models were established in wild-type, global GPR91 knockout, and cardiomyocyte-specific GPR91 knockout mice with or without succinate supplementation. Cardiac structure, function, and metabolic phenotypes were assessed using echocardiography, histology, and molecular assays. Transcriptome sequencing of myocardial tissues was performed to identify succinate-GPR91-dependent signaling pathways. Mechanistic studies in isolated cardiomyocytes were conducted to validate pathway regulation and clarify downstream molecular mechanisms. Rescue experiments were further carried out to confirm the functional relevance of succinate-GPR91 signaling in cardiomyocyte metabolism and HFpEF progression. Results: Cardiac succinate levels and GPR91 expression were markedly decreased in HFpEF mice. Succinate supplementation restored systemic metabolism, improved diastolic function, and attenuated myocardial hypertrophy and fibrosis in wild-type (WT) HFpEF mice, but these protective effects were lost in both global Gpr91⁻/⁻ and cardiomyocyte-specific Gpr91 ΔCM knockouts. Transcriptomic analysis demonstrated that succinate activated AMPK signaling and enriched pathways related to glucose-lipid metabolism and NAD⁺ biosynthesis in Gpr91 fl/fl but not in Gpr91 ΔCM hearts. Mechanistically, succinate enhanced AMPK phosphorylation and NAD⁺ production via Gq-mediated signaling, thereby promoting metabolic reprogramming. Conclusion: These findings identify the succinate-GPR91 axis as a critical regulator of cardiometabolic homeostasis and a potential therapeutic target in HFpEF.

DOI: https://doi.org/10.21203/rs.3.rs-7556256/v1

Metabolism. 2025 Sep 18. pii: S0026-0495(25)00264-1. [Epub ahead of print] 156395

Enhancing cardiac serine biosynthesis mitigates the progression of dilated cardiomyopathy.

Maryam Kay, Anne-Maj Samuelsson, Nike Bharucha, Xueyi Li, Rohin Ramchandani, Rachel E Baum, Diego Ruiz, Aurélie Laguerre, Sherin Lajevardi, Shrikaar Kambhampati, Christian M Metallo, Michael S Kapiloff, Ioannis Karakikes.

Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. However, disease-modifying therapies remain limited. Metabolic dysfunction has emerged as a key driver of DCM pathogenesis, and impaired serine biosynthesis, catalyzed by the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH), has recently been identified as a potential therapeutic target. Here, we evaluated the therapeutic potential of increasing serine biosynthesis through AAV9-mediated PHGDH gene augmentation in a transgenic TM54 mouse model of DCM with established pathology. Longitudinal echocardiography showed preserved systolic function and prevented ventricular dilatation in TM54 mice treated with AAV9-PHGDH compared to AAV9-GFP controls. Histological analysis revealed reduced myocardial fibrosis and cardiomyocyte hypertrophy in AAV9-PHGDH-treated TM54 hearts, indicating a reversal of pathological remodeling. Metabolic profiling, including targeted metabolomics and in vivo 13C-glucose tracing analysis, revealed that serine levels increased in hearts treated with AAV9-PHGDH, accompanied by decreases in glucose-derived pyruvate and lactate. At the same time, mitochondrial oxidative metabolism remained intact, indicating a shift of glycolytic carbon towards serine biosynthesis. Collectively, these findings show that enhancing cardiac serine synthesis through PHGDH gene augmentation therapy preserves contractile function and mitigates disease progression in vivo, suggesting a novel metabolic therapeutic strategy for DCM.

Keywords: Dilated cardiomyopathy; Gene therapy; Metabolic therapy; PHGDH; Serine biosynthesis

DOI: https://doi.org/10.1016/j.metabol.2025.156395

Circ Res. 2025 Sep 26. 137(8): 1089-1091

Unlocking Mitochondrial Potential: DWORF to the Rescue in Heart Failure.

Mahmoud H Elbatreek, David J Lefer.

Keywords: Editorials; heart failure; homeostasis; myocardial infarction; prognosis

DOI: https://doi.org/10.1161/CIRCRESAHA.125.327249

Biomedicines. 2025 Aug 26. pii: 2080. [Epub ahead of print]13(9):

Targeting Cardiac Metabolism in Heart Failure with PPARα Agonists: A Review of Preclinical and Clinical Evidence.

Carla Handford, Laura Stirling-Barros, Mahboube Ganji-Arjenaki, Masliza Mahmod, Milad Nazarzadeh, Malgorzata Wamil.

Background and objective: Heart failure (HF) is associated with high morbidity, mortality, and healthcare costs. Its prevalence continues to rise, particularly in the context of ageing populations and increasing rates of metabolic comorbidities such as type 2 diabetes and obesity. We aimed to assess the therapeutic potential of repurposing PPARα agonists for the treatment of HF. Method: We conducted a comprehensive literature review to evaluate preclinical and clinical evidence investigating the potential of PPARα agonist drugs in reducing HF. We did not apply any restrictions on the study design. Results: The current body of evidence consists of preclinical mechanistic studies, emerging pharmacogenetic data, and post hoc analyses of large randomised clinical trials (RCTs) that included HF endpoints. No dedicated, HF-specific RCTs of PPARα agonists were identified. These studies support the hypothesis that PPARα agonists may link metabolic modulation with cardiac remodelling. Preclinical models demonstrate potential therapeutic benefits, such as enhanced myocardial energy metabolism and attenuation of fibrosis and inflammation, as well as context-dependent risks, including possible deleterious effects in advanced HF or off-target mechanisms. Prior failures of fibrates to improve cardiovascular outcomes in some trials and concerns in PPARα-deficient states underscore the complexity of metabolic therapies in HF. These findings support a more stratified, phenotype-driven approach to therapy. RCTs specifically designed to evaluate HF outcomes are essential to clarify whether PPARα agonists can complement established neurohormonal treatments, particularly in the context of the rising burden of HFpEF associated with obesity and type 2 diabetes. Conclusions: PPARα agonists represent a promising class within the emerging therapeutic framework of metabolic heart failure. They are inexpensive, generally well tolerated, and address several pathophysiological mechanisms of HF. Preliminary evidence suggests that fenofibrate may delay or prevent HF in high-risk diabetic populations. However, rigorous, dedicated trials are needed to establish their clinical utility.

Keywords: PPARα agonists; diabetes; fenofibrate; fibrates; heart failure; left ventricular hypertrophy; myocardial fibrosis

DOI: https://doi.org/10.3390/biomedicines13092080

Cardiovasc Endocrinol Metab. 2025 Dec;14(4): e00344

Glucagon-like peptide-1 receptor agonists and obesity paradox in heart failure with preserved ejection fraction: a systematic review.

Darshan Hullon, Karolina Janiec, Violetta Florova, Adam Trach, Yelizaveta Volkova, Ruslan Mnevets.

Heart failure with preserved ejection fraction (HFpEF) is associated with obesity, inflammation, and cardiac metabolism. While obesity contributes to HFpEF, the 'obesity paradox' suggests that higher BMI may correlate with better outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have cardiovascular benefits through weight loss, anti-inflammatory effects, and improved myocardial function. This systematic review involved randomized trials and cohort studies from 2015 to 2024, assessing GLP-1 RAs in patients with obese HFpEF (BMI ≥ 30 kg/m²). Outcomes included heart failure hospitalizations, mortality, exercise capacity, and quality of life. Eighteen studies involved over 22 000 participants. GLP-1 RAs, especially semaglutide and tirzepatide, consistently reduced weight, inflammation (C-reactive protein), and myocardial stress (N-terminal pro B-type natriuretic peptide) while improving 6-min walk distance and Kansas City Cardiomyopathy Questionnaire scores, uniformly across BMI groups. GLP-1 RAs counter the metabolic burden of obesity in HFpEF while preserving hemodynamic benefits, offering a promising therapeutic option.

Keywords: glucagon-like peptide-1 receptor agonists; heart failure with preserved ejection fraction; obesity

DOI: https://doi.org/10.1097/XCE.0000000000000344

Cureus. 2025 Aug;17(8): e90684

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Non-diabetic Heart Failure: A Systematic Review of Randomized Controlled Trials and Real-World Evidence.

Mohammed O Ibrahim, Osama M Mohamed, Nagwa M Ali.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially developed to improve glycemic control in patients with type 2 diabetes. More recently, growing evidence has highlighted their cardiovascular benefits, particularly in patients with heart failure (HF), irrespective of diabetic status. This systematic review evaluates the efficacy and safety of SGLT2i, including dapagliflozin and empagliflozin, in non-diabetic patients with HF across different phenotypes, namely heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). A comprehensive literature search was conducted in PubMed, Scopus, and Embase for studies published between January 1, 2015, and January 15, 2024, in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies included adult patients with HF, reported outcomes for non-diabetic subgroups, and assessed treatment with SGLT2i. Six studies met the inclusion criteria: four randomized controlled trials (RCTs), one pooled patient-level analysis, and one observational cohort study involving 16,264 non-diabetic patients. A pooled patient-level analysis incorporated data from DAPA-HF and DELIVER; to avoid duplication, only DAPA-HF was analyzed individually, while DELIVER was included solely within the pooled dataset. SGLT2i use was associated with lower cardiovascular mortality (hazard ratio (HR): 0.73-0.86) and reduced HF hospitalization, with consistent benefits in both HFrEF and HFpEF. Adverse events such as hypoglycemia, volume depletion, and infections were uncommon and typically mild, although genital infections were more frequent than placebo, and severe adverse events were not increased. Due to heterogeneity in study designs, outcome definitions, and HF phenotypes, quantitative meta-analysis was not feasible. A structured qualitative synthesis was performed. To our knowledge, this is one of the first systematic reviews to comprehensively evaluate the use of SGLT2i in non-diabetic patients with HF across phenotypes. The findings reinforce the role of SGLT2i as a foundational therapy in non-diabetic HF and highlight the need for broader implementation in practice.

Keywords: dapagliflozin; empagliflozin; heart failure; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; non-diabetic patients; sglt2 inhibitors; sodium-glucose cotransporter-2 (sglt2) inhibitors; systematic review

DOI: https://doi.org/10.7759/cureus.90684