bims-hafaim 2025-06-22 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–06–22
eight papers selected by
Kyle McCommis, Saint Louis University

BCAA catabolism targeted therapy for heart failure with preserved ejection fraction.
Energy metabolism in cardiovascular diseases: unlocking the hidden powerhouse of cardiac pathophysiology.
The Cardiac and Hemodynamic Effects of Ketone Bodies Are Abnormal in Patients With Type 1 Diabetes: A Randomized Controlled Trial.
Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Heart Failure With Preserved Ejection Fraction: A Systematic Review.
Tirzepatide, a dual GIP/GLP1-receptor co-agonist preserves cardiac function and improves survival in angiotensin II-induced heart failure model in mice: comparison to liraglutide.
The crosstalk between immune activation and metabolism in heart failure. A scientific statement of the Heart Failure Association of the ESC.
Modulation of PPAR-α and PPAR-γ Influences Cardiomyocyte Growth and Cardiac Remodeling.
Short-term dietary methionine restriction with high fat diet counteracts metabolic dysfunction in male mice.

Theranostics. 2025 ;15(13): 6257-6273

BCAA catabolism targeted therapy for heart failure with preserved ejection fraction.

Meng Wang, Zhao Liu, Shuxun Ren, Jinyun Zhu, Norihiko Morisawa, Geok Lin Chua, Xuewen Zhang, Yun Ka Wong, Liping Su, Ming Xiang Wong, Jieping Yang, Marc Titze Jens, Zhaoping Li, Haipeng Sun, Yibin Wang, Christoph D Raul, Sanjiv J Shah, Chen Gao, Yunxia Liu.

  Rationale: Heart failure with preserved ejection fraction (HFpEF) is a major unmet medical need with limited effective treatments. A significant contributing factor to HFpEF, a multifactorial disease, is underlying metabolic dysfunction. While much of the prior research has been on glucose and fatty acid metabolic defects in the pathogenesis of HFpEF, other metabolic activities remain under investigated. Methods: System-based metabolomics and targeted mass spectrometry were employed to analyze serum and tissue samples from a deep-phenotyped human HFpEF cohort. A preclinical mouse model of HFpEF was developed by combined administration of a high-fat diet (HFD) and the nitric oxide (NO) synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME). The branched-chain amino acid (BCAA) catabolic activities were enhanced by genetic inactivation of branched-chain ketoacid-dehydrogenase kinase (BCKDK) or treatment with BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), a highly selective inhibitor of BCKDK. Cardiac function, myocardial remodeling and insulin signaling in the left ventricle were assessed across all experimental cohorts. Results: The systems-based metabolomics analysis of the deep-phenotyped HFpEF and non-HFpEF patients revealed that abnormal circulating BCAA levels were significantly associated with adverse outcomes. In the rodent model of HFpEF, significant impairment of BCAA catabolic activities in the heart and abnormal circulating BCAA levels were also observed. In adult mice, inducible knockout of BCKDK, the rate-limiting negative regulator of BCAA catabolic flux, markedly augmented BCAA catabolic activities. Compared with the controls, BCKDK inactivation blunted diastolic dysfunction, cardiac hypertrophy and myocardial remodeling in response to chronic treatment with HFD/L-NAME. This functional amelioration was associated with improved insulin signaling in the myocardium and reduced S-nitrosylation of cardiac proteins, without any impact on systemic blood pressure. Finally, pharmacological inhibition of BCKDK in HFpEF mice significantly reversed the diastolic dysfunction and cardiac hypertrophy associated with HFpEF. Conclusions: Our study provides the first proof-of-concept evidence that global catabolic impairment of BCAAs is an important pathogenic contributor and metabolic signature of HFpEF and restoring BCAA catabolic flux could be an efficacious therapeutic strategy for HFpEF.

Keywords:  BCAA metabolism; BT2; HFpEF; heart failure; insulin resistance

DOI:  https://doi.org/10.7150/thno.105894
Front Endocrinol (Lausanne). 2025 ;16 1617305

Energy metabolism in cardiovascular diseases: unlocking the hidden powerhouse of cardiac pathophysiology.

Li Chen, Mingtai Chen, Xinrui Yang, Yuanli Hu, Caiwei Qiu, Youyou Fu, Xiaoyu Lan, Gang Luo, Qiuyu Liu, Mengnan Liu.

  Cardiovascular diseases (CVDs) remain the leading cause of global mortality, yet their pathogenesis has not been fully elucidated, particularly regarding the role of abnormal energy metabolism. Major outstanding questions pertain to the dynamic regulation of metabolic reprogramming and its complex interplay with mitochondrial dysfunction. Previous studies have demonstrated that the heart, as a high-energy-demand organ, relies on the dynamic equilibrium of substrates such as fatty acid (FA) and glucose to sustain adenosine triphosphate (ATP) production. Metabolic disturbances-characterized by suppressed FA oxidation and aberrant activation of glycolysis-directly contribute to the pathological progression of various CVDs, including heart failure (HF), atherosclerosis, and myocardial infarction(MI), through mechanisms involving oxidative stress, inflammatory responses, and an energy crisis. This review systematically examines the core pathways of cardiac energy metabolism (e.g., mitochondrial oxidative phosphorylation (OXPHOS), regulation of glucose and lipid metabolism) and their dysregulation in disease states, while evaluating intervention strategies targeting metabolic pathways, such as mitochondrial function enhancement and substrate utilization modulation. Future research directions emphasize the integration of metabolomics with clinical translational studies to comprehensively decipher the multidimensional regulation of metabolic networks, thereby facilitating the development of novel precision therapeutic targets.

Keywords:  cardiovascular diseases (CVDs); energy metabolism; metabolic reprogramming; mitochondrial dysfunction; precision therapeutic targets

DOI:  https://doi.org/10.3389/fendo.2025.1617305
Diabetes. 2025 Jun 17. pii: db250243. [Epub ahead of print]

The Cardiac and Hemodynamic Effects of Ketone Bodies Are Abnormal in Patients With Type 1 Diabetes: A Randomized Controlled Trial.

Kristoffer Berg-Hansen, Maj Bangshaab, Nigopan Gopalasingam, Roni Nielsen, Mads Svart, Nikolaj Rittig, Niels Møller, Henrik Wiggers.

ARTICLE HIGHLIGHTS: The diabetic heart has reduced ketone utilization due to impaired ketolytic enzyme activity. In a randomized, controlled, crossover trial, we investigated whether the cardiac response to 3-hydroxybutyrate infusion is impaired in type 1 diabetes. The response on cardiac output was blunted by 80% in type 1 diabetes, with no improvement in systolic function and left ventricular work efficiency was reduced. These findings suggest impaired cardiac ketone metabolism may have clinical significance and could contribute to diabetic cardiomyopathy.

DOI: https://doi.org/10.2337/db25-0243
Cureus. 2025 May;17(5): e84129

Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Heart Failure With Preserved Ejection Fraction: A Systematic Review.

María Victoria Santos Guzmán, Daimi Rivera, Isabella Marian Reyna Guerrero, Alfida Luisa Fernandez Rodriguez, Rania Azcona, Diego Escobar Batista, Gabriela Montano Diaz, Luis Carlos García Zuluaga, Victor Santos Rosario.

  Heart failure with preserved ejection fraction (HFpEF) represents a growing clinical challenge with limited therapeutic options. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as a promising intervention; however, their impact across diverse HFpEF populations requires further clarification. We conducted a systematic review of four completed randomized controlled trials (RCTs) - CANDLE (Canagliflozin Anti-inflammatory and Metabolic Effects), EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction), the JCI 2021 Empagliflozin HFpEF trial (a Japan Cardiovascular Initiative study assessing empagliflozin in heart failure with preserved ejection fraction), and a multi-agent SGLT2 inhibitor study (empagliflozin, dapagliflozin, and canagliflozin vs. standard of care) - plus one ongoing multicenter study, HELD-HF (Heart Failure with Preserved Ejection Fraction and Empagliflozin in a Long-term Diabetes Population), encompassing approximately 13,400 participants with HFpEF, to evaluate the efficacy and safety of SGLT2 inhibition. In EMPEROR-Preserved (n = 5,792; median follow-up 26.2 months), empagliflozin reduced heart failure hospitalizations from 11.1% to 8.3% and cardiovascular mortality from 16.2% to 13.4% (hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.68-0.84). In a multi-agent trial (n = 1,253; 18 months), SGLT2 inhibitors lowered cardiovascular mortality (4% vs. 5%) and HF hospitalizations (7% vs. 10%), with an absolute risk reduction of 1% and 3%, respectively, and improved patient-reported quality of life (mean Kansas City Cardiomyopathy Questionnaire (KCCQ) score increase of 8 points). Functional capacity, assessed by the 6-minute walk test, improved by a mean of 25-30 m across completed studies, and KCCQ scores rose by 5-10 points. N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels decreased by 10-20% (e.g., -10.4% vs. comparator in CANDLE). Safety profiles were favorable: serious adverse event rates were comparable to placebo (≈12% vs. 13%), genital infections occurred in ~2.5% vs. 0.5%, and symptomatic hypotension in 7% vs. 5% of participants. The ongoing HELD-HF trial (n = 112; 24 weeks) will further elucidate effects on left ventricular mass index and NT-proBNP in dialysis-dependent HFpEF patients. These findings support the integration of SGLT2 inhibitors into HFpEF management and highlight the need for further large-scale, long-term studies to optimize their therapeutic application.

Keywords:  cardiovascular mortality; dapagliflozin; heart failure hospitalization; heart failure with preserved ejection fraction; quality of life; randomized controlled trial; sodium–glucose transporter 2 inhibitors

DOI:  https://doi.org/10.7759/cureus.84129
Cardiovasc Diabetol. 2025 Jun 14. 24(1): 253

Tirzepatide, a dual GIP/GLP1-receptor co-agonist preserves cardiac function and improves survival in angiotensin II-induced heart failure model in mice: comparison to liraglutide.

Zsombor I Hegedűs, Márk E Jakab, Tamás G Gergely, Nabil V Sayour, Andrea Kovács, Sára Antal, Tamás Kovács, Péter Ferdinandy, Zoltán V Varga, Viktória E Tóth.

   BACKGROUND: Incretin analogues, used for the treatment of type 2 diabetes mellitus and obesity, such as GLP1-receptor agonist liraglutide (Lira) have been shown to reduce major adverse cardiac events in recent clinical trials of heart failure. Tirzepatide (TZP), a dual GIP/GLP1-receptor agonist has shown promising results in the SUMMIT trial as improved cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF). However, data regarding their use in heart failure with reduced ejection fraction (HFrEF) is lacking. We performed a head-to-head comparative study in a mouse model of non-ischaemic cardiac injury induced by continuous angiotensin II (AngII) infusion, as AngII is a key driver of both heart failure forms.
METHODS: Osmotic minipumps were inserted for subcutaneous (s.c.) administration of AngII (1.5 mg/kg/day) in 5-month-old male Balb/c mice or sham surgery was performed. Animals were treated with vehicle (Veh), Lira (300 µg/day i.p.) or TZP (48 µg/day s.c.) for 14 days in the following groups: Sham/Veh (n = 7), AngII/Veh (n = 15), Sham/Lira (n = 7), AngII/Lira (n = 15), Sham/TZP (n = 8), AngII/TZP (n = 15). Cardiac structural, functional and molecular characteristics were assessed by echocardiography, ECG, immunohistochemistry, flow cytometry and qRT-PCR.
RESULTS: Mortality was significantly higher in AngII/Veh animals compared to controls, while AngII/TZP mice showed significantly reduced mortality after 14 days of treatment. Both Lira and TZP caused significant weight reduction compared to controls. AngII given alone also reduced body mass, and this reduction was further enhanced by TZP. Treatment with both compounds preserved cardiac systolic and diastolic function compared with AngII/Veh animals, as shown by normal ejection fraction and E/e', respectively. Both Lira and TZP decreased the AngII-induced elevation of cardiac fibrosis and hypertrophy markers, including Ctgf, Col1a1, Col3a1, and Nppa, while TZP also reduced the elevated Nppb level. TZP also reduced systemic inflammation, as shown by the reduction in serum CRP levels.
CONCLUSIONS: Lira and TZP preserved cardiac function and decreased markers of hypertrophy and fibrosis in mice with AngII-induced heart failure, whereas TZP also significantly decreased mortality. In addition to HFpEF, the use of incretin analogues may also be of clinical relevance in the treatment of HFrEF. However, as patients with heart failure, AngII level is elevated and can cause weight loss/cachexia, the usage of incretin analogues to treat non-obese heart failure patients should be considered.

Keywords:  HFrEF; Heart failure; Incretin analogues; Liraglutide; Tirzepatide

DOI:  https://doi.org/10.1186/s12933-025-02806-5
Eur J Heart Fail. 2025 Jun 16.

The crosstalk between immune activation and metabolism in heart failure. A scientific statement of the Heart Failure Association of the ESC.

Gabriele Fragasso, Davide Stolfo, Markus S Anker, Antoni Bayes-Genis, Ovidiu Chioncel, Stephane Heymans, Pardeep S Jhund, Basil S Lewis, Gary D Lopaschuk, Lars H Lund, Arantxa Gonzalez, Matteo Pagnesi, Gabriele Giacomo Schiattarella, Carlo Gabriele Tocchetti, Peter van der Meer, Sophie Von Linthout, Sven Wassmann, B Daan Westenbrink, Marco Metra, Giuseppe M C Rosano, Gianluigi Savarese.

  A better understanding of additional mechanisms of heart failure (HF) progression may allow a different and more complete phenotyping of the disease and identification of novel therapeutic targets. Persistent latent myocardial inflammation/immune activation in HF may represent an attempt to restore tissue homeostasis in the failing heart, where cardiomyocytes and immune cells undergo metabolic reprogramming, which allows them to deal with decreased availability of nutrients and oxygen. This status can trigger a metabolic crosstalk between immune cells and cardiomyocytes which, depending on the outcome, can either perpetuate the maladaptive remodelling of the heart, or determine an adaptive response. Therefore, the interplay between immune activation and metabolism is gaining recognition as a potential therapeutic framework. On these premises, future studies addressing novel HF treatments should attempt to evaluate the potential therapeutic role of direct metabolic and immunological crosstalk modulation. The aim of the present scientific statement from the Heart Failure Association of the ESC is to summarize the current evidence for the connection between inflammatory and immune activation and metabolic adaptation in the onset and progression of HF, in order to promote future strategies for the development of targeted-disease preventive and therapeutic measures.

Keywords:  Aging; Heart failure; Immunometabolism; Inflammation; Maladaptive; Myocardial Metabolism; Therapy

DOI:  https://doi.org/10.1002/ejhf.3703
IUBMB Life. 2025 Jun;77(6): e70035

Modulation of PPAR-α and PPAR-γ Influences Cardiomyocyte Growth and Cardiac Remodeling.

Qinkao Xuan, Jin Li, Zexiong Feng, Li Zhu, Tingbo Jiang, Hongxia Li, Ming Liu, Xiaodong Qian, Xiao Ma.

  Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, are key regulators of cardiac energy metabolism and have been implicated in cardiac remodeling. However, their roles in cardiomyocyte proliferation and hypertrophy remain incompletely understood. In this study, we investigated the effects of PPAR-α and PPAR-γ modulation on neonatal rat cardiomyocytes (NRCMs) using pharmacological agonists (WY-14643 for PPAR-α and pioglitazone for PPAR-γ) and inhibitors (MK-886 for PPAR-α and GW9662 for PPAR-γ), as well as siRNA-mediated knockdown approaches. Cardiomyocyte proliferation and hypertrophy were assessed by immunofluorescence, cell size measurements, and proliferation assays. Our findings demonstrate that PPAR-α activation significantly promotes cardiomyocyte proliferation and reduces hypertrophy, whereas PPAR-α inhibition induces hypertrophic changes and suppresses proliferation. Similarly, PPAR-γ activation enhances both proliferation and hypertrophy of cardiomyocytes, suggesting its involvement in physiological hypertrophy and a potential protective role in pathological remodeling. In contrast, pharmacological activation or genetic inhibition of PPAR-δ showed no significant effects on cardiomyocyte proliferation or hypertrophy, highlighting its distinct role in metabolic homeostasis rather than structural remodeling. PPAR-α and PPAR-γ play distinct but complementary roles in regulating cardiomyocyte proliferation and hypertrophy. These results suggest that targeting PPAR-α and PPAR-γ may represent promising therapeutic strategies for cardiac hypertrophy and heart failure. Further in vivo studies are warranted to clarify their molecular mechanisms and potential clinical applications.

Keywords:  PPAR‐α; PPAR‐γ; cardiac hypertrophy; cardiac remodeling; cardiomyocyte proliferation

DOI:  https://doi.org/10.1002/iub.70035
Physiol Rep. 2025 Jun;13(12): e70405

Short-term dietary methionine restriction with high fat diet counteracts metabolic dysfunction in male mice.

Marissa I McGilvrey, Bethany Fortier, Diana Cooke, Maryam A Mahdi, Benjamin Tero, Christian M Potts, Abigail Kaija, Larisa Ryzhova, Carolina Cora, Adam Richardson, Douglas Guzior, Ilka Pinz, Calvin Vary, Robert A Koza, Gene Ables, Lucy Liaw.

  Dietary methionine restriction (MetR) promotes metabolic health, and we tested the impact of short durations of MetR on high fat diet (HFD)-induced metabolic dysfunction with the maintenance of HFD. Male C57BL/6J mice were fed HFD from 10 to 25 weeks of age, then maintained on HFD or fed HFD with 80% reduced methionine (HFD-MetR) for 3, 5, or 10 days. Blood, liver, adipose tissue, and aortae underwent phenotypic assessment, proteomics, and metabolomics. HFD-MetR induced rapid weight loss and robust metabolic improvement within 10 days. Significant reductions in body weight, circulating triglycerides, glucose, insulin, adipokines and hepatokines reflected metabolic health. Proteomics revealed enriched metabolic signatures in perivascular adipose tissue (PVAT) and structural remodeling signatures in aorta. Metabolomics identified a cardioprotective signature in blood plasma, and activated mitochondrial activity and energy production in liver and brown adipose tissue. HFD-MetR reversed metabolic dysfunction, and novel proteomic and metabolomic signatures were identified. Multi-organ molecular changes in lipid metabolism, mitochondrial function, and bioenergetics are predicted to impact adipose tissue and liver function and cardiovascular health. Our identification of rapid changes in protein and metabolite signatures with accelerated restoration of metabolic health can be leveraged to evaluate biomarkers of metabolic health and disease in a translational context.

Keywords:  adipose tissue; high fat diet; metabolomics; methionine restriction; proteomics

DOI:  https://doi.org/10.14814/phy2.70405