bims-hafaim 2025-03-02 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–03–02
seven papers selected by
Kyle McCommis, Saint Louis University

Efficacy of GLP-1 Receptor Agonists in Patients with Heart Failure and Mildly Reduced or Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.
Metabolic flexibility and reverse remodelling of the failing human heart.
Integrated Omics Insights into Dapagliflozin Effects in Sepsis-Induced Cardiomyopathy.
High-fat intake during lactation ameliorates cardiac fatty acid metabolic disorders and dysfunction in mouse offspring undergoing prenatal poly (I:C) stimulation.
Cardiac energy metabolism is decreased in male volunteers with prediabetes and does not normalize during the day.
PDE4D inhibition ameliorates cardiac hypertrophy and heart failure by activating mitophagy.
Short-Chain Fatty Acids and Their Metabolic Interactions in Heart Failure.

J Card Fail. 2025 Feb 22. pii: S1071-9164(25)00091-0. [Epub ahead of print]

Efficacy of GLP-1 Receptor Agonists in Patients with Heart Failure and Mildly Reduced or Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.

Saad Ahmed Waqas, Muhammad Umer Sohail, Muhammad Saad, Abdul Mannan Khan Minhas, Stephen J Greene, Marat Fudim, Gregg C Fonarow, Dmitry Abramov, Muhammad Shahzeb Khan, Raheel Ahmed.

BACKGROUND: Heart failure with mildly reduced or preserved ejection fraction (HFpEF) accounts for over half of heart failure cases, with obesity playing a key role. Residual risk remains high despite available therapies. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential cardiometabolic benefits, but their role in HFpEF remains unclear.
METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GLP-1RAs in HFpEF was conducted. Studies evaluating GLP-1RA in combination with glucose-dependent insulinotropic polypeptide (GIP) were also included. The analyzed outcomes included cardiovascular (CV) death, worsening heart failure (HF) events, and their composite. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model.
RESULTS: Six RCTs with 8,788 patients were included. GLP-1RAs significantly reduced the composite outcome of CV death or worsening HF events (HR: 0.68 [0.51-0.89], p = 0.006, I² = 47%) as well as worsening HF events alone (HR: 0.56 [0.38-0.82], p = 0.003, I² = 51%). No significant reduction was observed for CV death alone (HR: 0.86 [0.67-1.12], p = 0.27, I² = 0%).
CONCLUSION: GLP-1RAs reduce worsening HF events and the composite of CV death or worsening HF in HFpEF, particularly in patients with obesity or diabetes. These findings support their role as a promising therapy requiring further HFpEF-focused trials.

DOI: https://doi.org/10.1016/j.cardfail.2025.01.022
Eur Heart J. 2025 Feb 25. pii: ehaf033. [Epub ahead of print]

Metabolic flexibility and reverse remodelling of the failing human heart.

Peregrine G Green, William D Watson, Benjamin M Bussmann, Giovanni Luigi De Maria, Stefan Neubauer, Andrew J M Lewis, Oliver J Rider, Neil Herring.

   BACKGROUND AND AIMS: Cardiac resynchronization therapy (CRT) produces long-term reverse remodelling which requires greater adenosine triphosphate delivery to the contractile machinery. Whilst the heart retains some metabolic flexibility in non-ischaemic cardiomyopathy, whether this correlates with reverse remodelling is unknown. This study investigated whether CRT acutely changes cardiac substrate uptake, and whether this translates to favourable reverse remodelling.
METHODS: The effect of CRT on cardiac substrate uptake was assessed via direct coronary flow and arteriovenous measurements, with metabolomic/lipidomic analysis on infusions of insulin/glucose and intralipid. Cardiac function was assessed with left ventricular pressure-volume loops during implantation, and cardiac magnetic resonance before and 6 months following CRT, with and without biventricular pacing.
RESULTS: Regardless of substrate infusion, CRT acutely improved stroke work without increasing O2 uptake on both insulin/glucose (by 34%, P = .05) and intralipid (by 36%, P = .03). This was followed by increased fatty acid (FA) uptake on insulin/glucose (R = 0.89, P = .03) and increased β-hydroxybutyrate uptake (R = 0.81, P = .05) during intralipid infusion. After 6 months, there was a 48% (P < .001) reduction in left ventricular end diastolic volume, beyond that achievable by acutely shortening or lengthening QRS duration. Reverse remodelling significantly correlated with increased FA uptake with CRT on insulin/glucose (R = 0.71, P = .05) driven by long and medium chain uptake, and increased ketone uptake with CRT on intralipid (R = 0.79, P = .05).
CONCLUSIONS: CRT acutely alters the metabolic phenotype of non-ischaemic cardiomyopathy towards a more physiological picture of FA uptake which correlates with reverse remodelling. Retained metabolic flexibility may therefore be critical for subsequent reverse remodelling.

Keywords:  Metabolism; Non-ischaemic cardiomyopathy; Resynchronization; Reverse remodelling

DOI:  https://doi.org/10.1093/eurheartj/ehaf033
Biomolecules. 2025 Feb 14. pii: 286. [Epub ahead of print]15(2):

Integrated Omics Insights into Dapagliflozin Effects in Sepsis-Induced Cardiomyopathy.

Weiwei Lai, Li Liu, Shuhang Wang, Yancun Liu, Yanfen Chai.

   BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a life-threatening cardiac complication of sepsis with limited therapeutic options. Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has demonstrated cardioprotective effects in heart failure, but its role in mitigating sepsis-related cardiac dysfunction remains unclear.
METHODS: A retrospective cohort analysis was conducted to assess the impact of pre-hospital dapagliflozin use on major adverse cardiovascular events (MACEs) and survival in patients with SIC. Additionally, a murine SIC model was established using cecal ligation and puncture (CLP) to evaluate the effects of dapagliflozin on cardiac function, histopathology, and biomarkers of myocardial injury. Transcriptomic and metabolomic profiling, combined with multi-omics integration, was employed to elucidate the molecular mechanisms underlying dapagliflozin's cardioprotective effects.
RESULTS: In the clinical cohort, pre-hospital dapagliflozin use was associated with a significant reduction in the risk of MACE and improved survival outcomes. In the murine SIC model, dapagliflozin restored cardiac function, reduced biomarkers of myocardial injury, and alleviated histological damage. Multi-omics analysis revealed that dapagliflozin modulates inflammatory responses, enhances autophagy, and regulates metabolic pathways such as AMPK signaling and lipid metabolism. Key regulatory genes and metabolites were identified, providing mechanistic insights into the underlying actions of dapagliflozin.
CONCLUSIONS: Dapagliflozin significantly improves cardiac outcomes in sepsis-induced cardiomyopathy through the multi-level regulation of inflammation, energy metabolism, and cellular survival pathways. These findings establish dapagliflozin as a promising therapeutic strategy for SIC, offering translational insights into the treatment of sepsis-induced cardiac dysfunction.

Keywords:  cardioprotective mechanisms; dapagliflozin; metabolomics; sepsis-induced cardiomyopathy; transcriptomics

DOI:  https://doi.org/10.3390/biom15020286
Acta Pharmacol Sin. 2025 Feb 25.

High-fat intake during lactation ameliorates cardiac fatty acid metabolic disorders and dysfunction in mouse offspring undergoing prenatal poly (I:C) stimulation.

Liang Song, Meng Meng, Yan Ji, Jian Peng, Xiao Guan, Yao Yang, Xiao-Feng Yin, Tao Liu, Kun-Peng Tian, Qing-Hua Bi, Jun-Ping Wang, Xiao-Hui Li, Yue Cai, You-Cai Deng.

  Prenatal inflammation exposure (PIE) is associated with increased prevalence of cardiovascular diseases (CVDs) in offspring, including heart failure and hypertension. In this study, we investigated the molecular mechanisms underlying the prenatal programming of cardiac function. Pregnant mice were injected with poly (I:C) (20 mg/kg, i.p.) on day 10.5 of gestation. Mothers and pubs were fed with high-fat diet during lactation. Cardiac tissues of the offspring were collected for analysis. We found that prenatal poly (I:C) exposure significantly reduced fatty acid metabolism and impaired the homeostasis of energy metabolism in the heart tissues of offspring at the age of 4 weeks. RNA-sequencing analysis of the heart tissues revealed that prenatal poly (I:C) exposure resulted in decreased expression of the fatty acid oxidation-related enzymes and increased expression of glycolysis-related enzymes, enabling rewiring of energy metabolism. High-fat intake during lactation partially ameliorated cardiac fatty acid metabolism in the heart tissues and prevented cardiac dysfunction in offspring mice exposed to prenatal poly (I:C) at the age of 16 weeks. Collectively, abnormal cardiac fatty acid metabolism accounts for the prenatal poly (I:C) exposure-induced cardiac dysfunction, highlighting the potential of dietary interventions to prevent cardiac dysfunction for PIE offspring.

Keywords:  cardiac dysfunction; fatty acid metabolism; high-fat diet; poly (I:C); prenatal inflammation exposure

DOI:  https://doi.org/10.1038/s41401-025-01497-8
Physiol Rep. 2025 Mar;13(5): e70242

Cardiac energy metabolism is decreased in male volunteers with prediabetes and does not normalize during the day.

Vera H W de Wit-Verheggen, Jakob Wefers, Carlijn M E Remie, Patrick Schrauwen, Vera B Schrauwen-Hinderling, Tineke van de Weijer.

  Type 2 diabetes mellitus is characterized by a low cardiac energy status (PCr/ATP ratio), but it is unknown whether this also applies to prediabetes. Since PCr/ATP is correlated with elevated free fatty acids (FFA), a potentially lower PCr/ATP might be secondary to elevated FFA. To investigate this, we determined PCr/ATP and FFA levels in volunteers with prediabetes at two time-points during the day. Eight male volunteers with prediabetes underwent a MRI/MRS scan to determine left ventricular ejection fraction (LVEF) and PCr/ATP ratio at 7 am and at 5 pm. For reference, these results were compared to eight non-insulin resistant overweight or obese volunteers. Myocardial energy status was lower in the volunteers with prediabetes (PCr/ATP 1.03 ± 0.08) compared to non-insulin resistant overweight or obese volunteers (PCr/ATP 1.22 ± 0.04, p < 0.05), but FFA were not significantly different between groups. LVEF was similar in the volunteers with prediabetes compared to healthy overweight and obese volunteers (p = 0.23). Volunteers with prediabetes have a lower myocardial energy status in the morning compared to healthy overweight and obese volunteers, while cardiac function remained normal. In addition, no differences between morning and evening measurements of cardiac energy status and function were found.

Keywords:  PCr/ATP; cardiac energy status; prediabetes

DOI:  https://doi.org/10.14814/phy2.70242
Redox Biol. 2025 Feb 22. pii: S2213-2317(25)00076-X. [Epub ahead of print]81 103563

PDE4D inhibition ameliorates cardiac hypertrophy and heart failure by activating mitophagy.

Jing Fu, Congping Su, Yin Ge, Zhou Ao, Li Xia, Yingxiang Chen, Yizheng Yang, Shiwei Chen, Rui Xu, Xiaoyan Yang, Kai Huang, Qin Fu.

  Cyclic adenosine monophosphate (cAMP) plays a major role in normal and pathologic signaling in the heart. Phosphodiesterase 4 (PDE4) is a major PDE degrading cAMP in the heart. There are inconsistencies concerning the roles of the PDE4 isoforms 4B and 4D in regulation of cardiac function. Cardiac PDE4B overexpression is beneficial in remodeling and heart failure (HF), however, the effect of PDE4D and PDE4 inhibitor in HF remains unclear. We generated global and conditional cardiac-specific heterozygous PDE4D knockout mice and adeno-associated virus serotype 9-PDE4D overexpression to determine the role of PDE4D in cardiac hypertrophy and HF. PDE4D upregulation was observed in failing hearts from human and isoproterenol injection and TAC mice. In vitro, isoproterenol stimulation increased PDE4D expression via PKA but had no effect on PDE4B expression in cardiomyocytes. PDE4D overexpression per se induced oxidative stress, mitochondrial damage and cardiomyocyte hypertrophy by decreasing PINK1/Parkin-mediated mitophagy through inhibiting cAMP-PKA-CREB-Sirtuin1 (SIRT1) signaling pathway, while PDE4B overexpression did not affect CREB-SIRT1 pathway and mitophagy but exhibited a protective effect on isoproterenol-induced oxidative stress and hypertrophy in cardiomyocytes. PDE4D silencing or inhibition with PDE4 inhibitor roflumilast ameliorated isoproterenol-induced mitochondrial injury and cardiomyocyte hypertrophy. In vivo, ISO injection or TAC inhibited cardiac mitophagy and caused cardiac hypertrophy and HF, which were ameliorated by roflumilast or cardiac-specific PDE4D haploinsufficiency. Conversely, cardiac PDE4D overexpression suppressed cardiac mitophagy and abolished the protective effects of global PDE4D haploinsufficiency on TAC-induced cardiac hypertrophy and HF. In conclusion, these studies elucidate a novel mechanism by which sustained adrenergic stimulation contributes to cardiac hypertrophy and HF by increasing PDE4D via cAMP-PKA signaling, which in turn reduces cAMP-PKA activity, resulting in cardiomyocyte hypertrophy and mitochondrial injury via inhibition of CREB-SIRT1 signaling-mediated mitophagy. PDE4D inhibition may represent a novel therapeutic strategy for HF.

Keywords:  CREB; Heart failure; Hypertrophy; Mitophagy; PDE4D; PKA; Phosphodiesterase 4; SIRT1; cAMP

DOI:  https://doi.org/10.1016/j.redox.2025.103563
Biomedicines. 2025 Feb 03. pii: 343. [Epub ahead of print]13(2):

Short-Chain Fatty Acids and Their Metabolic Interactions in Heart Failure.

Laura Chulenbayeva, Argul Issilbayeva, Aliya Sailybayeva, Makhabbat Bekbossynova, Samat Kozhakhmetov, Almagul Kushugulova.

  Short-chain fatty acids (SCFAs), produced through fermentation of dietary fibers by gut bacteria, play a central role in modulating cardiovascular function and heart failure (HF) development. The progression of HF is influenced by intestinal barrier dysfunction and microbial translocation, where SCFAs serve as key mediators in the gut-heart axis. This review examines the complex metabolic interactions between SCFAs and other gut microbiota metabolites in HF, including their relationships with trimethylamine N-oxide (TMAO), aromatic amino acids (AAAs), B vitamins, and bile acids (BAs). We analyze the associations between SCFA production and clinical parameters of HF, such as left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and glomerular filtration rate (GFR). Gaining insights into metabolic networks offers new potential therapeutic targets and prognostic markers for managing heart failure, although their clinical significance needs further exploration.

Keywords:  NT-proBNP; gut microbiome; heart failure; left ventricular ejection fraction; short-chain fatty acids

DOI:  https://doi.org/10.3390/biomedicines13020343