bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2025–05–11
ten papers selected by
Kyle McCommis, Saint Louis University
  1. Revisiting the thrifty substrate hypothesis: Ketone bodies as cardioprotective fuels in diabetes and SGLT2 inhibitor therapy.
  2. The role of sphingolipids in heart failure.
  3. Linagliptin Exerts a Sex-Specific Effect on Cardiac Function, Collateralization, and Metabolism in a Swine Model of Cardiometabolic Disease.
  4. Valine acts as an early biomarker and exacerbates pathological cardiac hypertrophy by impairing mitochondrial quality control.
  5. SGLT2 Inhibitors in Heart Failure: Iron Mobilization at the Heart of the Matter.
  6. Comparative efficacy and safety of SGLT2 inhibitor class members in patients with heart failure and type 2 diabetes: A systematic review and network meta-analysis of randomized controlled trials.
  7. Intrinsic Ketogenic Capacity of the Heart: Mechanisms and Therapeutic Potential.
  8. Efficacy and safety of empagliflozin in acute heart failure: a systematic review and meta-analysis.
  9. Meta-analysis of the efficacy and safety of SGLT-2 inhibitors in patients with heart failure and type 2 diabetes mellitus.
  10. Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF.
  1. J Diabetes Investig. 2025 May 07.
    Revisiting the thrifty substrate hypothesis: Ketone bodies as cardioprotective fuels in diabetes and SGLT2 inhibitor therapy.
    Yoriyasu Suzuki, Tetsuya Amano.
      SGLT2 inhibitors increase circulating β-hydroxybutyrate (β-OH-B), a ketone body that may enhance cardiac efficiency in HFrEF. The "thrifty substrate hypothesis" suggests β-OH-B provides more ATP per oxygen consumed than glucose or fatty acids. Clinical studies by Nielsen et al. and Solis-Herrera et al. show that β-OH-B infusion improves cardiac output, ejection fraction, and myocardial blood flow in HFrEF patients-with and without diabetes-without increasing oxygen demand or reducing glucose uptake. These findings support β-OH-B as an additive metabolic fuel, highlighting the therapeutic potential of enhancing cardiac metabolic flexibility.
    DOI:  https://doi.org/10.1111/jdi.70068
  2. Eur Heart J Open. 2025 May;5(3): oeaf035
    The role of sphingolipids in heart failure.
    Rana Hamouche, Scott A Summers, William L Holland, Sutip Navankasattusas, Stavros G Drakos, Eleni Tseliou.
      Advanced heart failure (HF) is characterized by changes in the structure, function, and metabolism of cardiac muscle. As the disease progresses, cardiomyocytes shift their ATP production from fatty acid oxidation to glycolysis. This shift results in an accumulation of lipid metabolites, particularly sphingolipids, which can disrupt normal cellular function and contribute to cardiac dysfunction. In animal models of obesity, accumulation of toxic sphingolipid metabolites in the heart has been described as cardiac lipotoxicity. In humans, HF is classified into two groups based on ejection fraction (EF): HF with reduced EF of less than 40% (HFrEF) and HF with preserved EF of greater than 50% (HFpEF). Despite shared risk factors and comorbidities, the structural and cellular differences between HFrEF and HFpEF distinguish them as separate conditions. Ceramides (Cer), a type of sphingolipid, have gained significant attention for their involvement in the development and prognosis of atherosclerotic disease and myocardial infarction, while sphingosine-1-phosphate, a downstream product of Cer, has shown cardioprotective properties. The aim of this review is to describe the role of sphingolipids in HF with reduced and preserved EF. By understanding the role of sphingolipids through animal and human studies, this review aims to pave the way for developing strategies that target abnormal signalling pathways in the failing heart, ultimately bridging the gap between scientific research and clinical applications.
    Keywords:  Ceramides; HFpEF; HFrEF; Heart failure; Sphingolipids
    DOI:  https://doi.org/10.1093/ehjopen/oeaf035
  3. J Thorac Cardiovasc Surg. 2025 Apr 17. pii: S0022-5223(25)00306-X. [Epub ahead of print]
    Linagliptin Exerts a Sex-Specific Effect on Cardiac Function, Collateralization, and Metabolism in a Swine Model of Cardiometabolic Disease.
    Kelsey C Muir, Dwight D Harris, Christopher Stone, Meghamsh Kanuparthy, Mark Broadwin, Jad Hamze, Frank W Sellke.
       OBJECTIVE: There are striking sex disparities among cardiometabolic disorders; however, the understanding of its underlying disease pathology remains uncertain, creating insufficient preventative and therapeutic approaches. Our study investigates the sex-specific response to the DPP-4 inhibitor, linagliptin, in a clinically meaningful model of metabolic syndrome and chronic myocardial ischemia.
    METHODS: Yorkshire swine were fed a high-fat diet for 5 weeks to induce metabolic syndrome and subsequently underwent placement of an ameroid constrictor to the left circumflex coronary artery (LCx), inducing chronic myocardial ischemia. Swine received either no drug (n=8; 4 female, 4 male) or 2.5mg linagliptin daily (n=8; 3 male, 5 female). Five weeks later, swine underwent hemodynamic measurements, microsphere injections to determine perfusion, and terminal harvest for left ventricular sectioning and molecular and proteomic analysis.
    RESULTS: Linagliptin-treated female swine demonstrated improved cardiac function compared to treated males and controls, including cardiac output, stroke work, and left ventricular end diastolic volume (all p<0.05). There was an increase in arteriolar and capillary density in treated females compared to control (p=0.002, p=0.031; respectively), with associated sex-specific changes in angiogenic proteins. Treated males had reduced glycogen stores by PAS staining compared to control (p=0.017). In contrast, female treated swine had a non-significant reduction in glycogen stores, and an upregulation of proteins associated with overall mitochondrial function and glycolysis.
    CONCLUSIONS: Linagliptin treatment resulted in a preferential improvement in left ventricular function, angiogenesis, and "metabolic flexibility" in female swine as compared to males and controls in the setting of metabolic syndrome and coronary artery disease.
    Keywords:  Angiogenesis; Coronary Artery Disease; DPP-4 Inhibition; Linagliptin; Sex Disparities
    DOI:  https://doi.org/10.1016/j.jtcvs.2025.04.017
  4. Atherosclerosis. 2025 Apr 26. pii: S0021-9150(25)00114-5. [Epub ahead of print]405 119216
    Valine acts as an early biomarker and exacerbates pathological cardiac hypertrophy by impairing mitochondrial quality control.
    Hongyu Kuang, Dan Li, Yunlin Chen, Hongmi Zou, Fang Li, Zhiyan Gong, Yuxiang Long, Hao Zhou, Huaan Du, Yuehui Yin.
       OBJECTIVE: Pathological cardiac hypertrophy is an independent risk factor for heart failure (HF). Early identification and timely treatment are crucial for significantly delaying the progression of HF.
    METHODS: Targeted amino acid metabolomics and RNA sequencing (RNA-seq) were combined to explore the underlying mechanism. In vitro, H9c2 cells were stimulated with angiotensin II (Ang II) or were incubated with extra valine after Ang II stimulation. The branched chain alpha-ketoate dehydrogenase kinase (Bckdk) inhibitor 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2) and rapamycin were utilized to confirm the role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in this process.
    RESULTS: A significant accumulation of valine was detected within hypertrophic hearts from spontaneously hypertensive rats (SHR). When branched chain amino acid (BCAA) degradation was increased by BT2, the most pronounced decrease was observed in the valine level (Δ = 0.185 μmol/g, p < 0.001), and cardiac hypertrophy was ameliorated. The role of imbalanced mitochondrial quality control (MQC), including the suppression of mitophagy and excessive mitochondrial fission, was revealed in myocardial hypertrophy. In vitro, high concentrations of valine exacerbated cardiomyocyte hypertrophy stimulated by Any II, resulting in the accumulation of impaired mitochondria and respiratory chain dysfunction. BT2, rapamycin, and mitochondrial division inhibitor 1 (Mdivi-1) all ameliorated MQC imbalance, mitochondrial damage and oxidative stress in hypertensive models with high valine concentration.
    CONCLUSION: Valine exacerbated pathological cardiac hypertrophy by causing a MQC imbalance, probably as an early biomarker for cardiac hypertrophy under chronic hypertension.
    Keywords:  Branched chain amino acids; Cardiac hypertrophy; Mitophagy; Oxidative stress; Valine
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2025.119216
  5. J Am Coll Cardiol. 2025 May 13. pii: S0735-1097(25)06071-1. [Epub ahead of print]85(18): 1771-1773
    SGLT2 Inhibitors in Heart Failure: Iron Mobilization at the Heart of the Matter.
    Kieran F Docherty.
      
    Keywords:  empagliflozin; erythroferrone; erythropoietin; heart failure; hepcidin; iron
    DOI:  https://doi.org/10.1016/j.jacc.2025.03.532
  6. Diabetes Res Clin Pract. 2025 May 03. pii: S0168-8227(25)00233-5. [Epub ahead of print]224 112219
    Comparative efficacy and safety of SGLT2 inhibitor class members in patients with heart failure and type 2 diabetes: A systematic review and network meta-analysis of randomized controlled trials.
    Angela Y Su, Molly M Csere, Ryan Shan, Vinay Pasupuleti, German V Valenzuela, Adrian V Hernandez.
      We conducted a systematic review with pairwise (PMA) and network meta-analyses (NMA) to evaluate sodium-glucose transport protein 2 inhibitor (SGLT2i) effects in patients with both heart failure (HF) and type 2 diabetes mellitus (T2DM). Five databases were searched up to April 15, 2025. Primary outcomes were all-cause mortality (ACM), cardiovascular death (CVD), all-cause hospitalization (ACH), and hospitalization for heart failure (HHF). SGLT2i class effects versus control were assessed via PMA and individual SGLT2i comparative efficacy via NMA plus ranking using p-scores. Seventeen randomized controlled trials (n = 17,809) were included. Arms included canagliflozin (n = 2), dapagliflozin (n = 6), empagliflozin (n = 6), ertugliflozin (n = 1), ipragliflozin (n = 1), sotagliflozin (n = 1), placebo (n = 13), and standard of care (n = 4). Compared to control, SGLT2i significantly reduced ACM (HR 0.87, 95 %CI 0.78 to 0.98, low quality of evidence [QoE]), ACH (HR 0.74, 95 %CI 0.62 to 0.88, high QoE), and HHF (HR 0.70, 95 %CI 0.63 to 0.77, low QoE); but not CVD (HR 0.87, 95 %CI 0.76 to 1.00, very low QoE). Canagliflozin ranked highest in decreasing ACM (p-score = 0.86), CVD (p-score = 0.82), and HHF (p-score = 0.88). In patients with HF and T2DM, SGLT2i class effects include ACM, ACH, and HHF reduction. Among SGLT2i, canagliflozin showed greatest ACM, CVD, and HHF benefit.
    Keywords:  Heart failure; Network meta-analysis; SGLT2 inhibitor; Systematic review; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.diabres.2025.112219
  7. Circ Res. 2025 May 09. 136(10): 1131-1133
    Intrinsic Ketogenic Capacity of the Heart: Mechanisms and Therapeutic Potential.
    Rosanna Caputo, Carolina Magdalen Greco.
      
    Keywords:  Editorials; fatty acids; glucose; heart failure; ketone bodies
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326560
  8. Future Cardiol. 2025 May 05. 1-7
    Efficacy and safety of empagliflozin in acute heart failure: a systematic review and meta-analysis.
    Noman Khalid, Muhammad Adil Afzal, Muhammad Abdullah, Ata-Ul Haiy, Yezin Shamoon, Sherif Elkattawy, Muhammad Aamir Laghari, Rahul Vasudev, Shamoon E Fayez, Yasotha Rajeswaran, Gregg M Lanier, Wilbert Aronow.
       BACKGROUND: Acute heart failure (AHF) is leading cause of hospitalization and mortality. Empagliflozin, a Sodium Glucose Co-transporter 2 inhibitor (SGLT-2i), has demonstrated benefits in HFrEF and HFpEF, but its role in AHF remains under-explored.
    OBJECTIVE: Assess safety and efficacy of empagliflozin in AHF.
    METHODS: A systematic review and meta-analysis adhering to PRISMA 2020 guidelines was conducted. A search on 25 February 2025, identified Phase IIb and III randomized controlled trials (RCTs) involving adults with AHF from databases like Medline®, Cochrane CENTRAL, Embase, and ClinicalTrials.gov. Outcomes included all-cause mortality, HF rehospitalization, cardiovascular deaths, and serious adverse events. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed with I2 and Cochrane Q-statistic.
    RESULTS: Three RCTs (n = 824) were included. Empagliflozin reduced all-cause mortality (OR: 0.47, 95% CI: 0.29-0.78, p = 0.004) and cardiovascular death (OR: 0.56, 95% CI: 0.38-0.82, p = 0.003) compared to placebo. It also lowered serious adverse events risk (OR: 0.62, 95% CI: 0.44-0.87, p = 0.005) without significantly increasing adverse effects such as acute kidney injury, diabetic ketoacidosis, hypotension, or urinary tract infections. Sensitivity analyses confirmed these findings.
    CONCLUSION: Empagliflozin reduces mortality in AHF with a favorable safety profile, highlighting need for further trials.
    Keywords:  Empagliflozin; SGLT2i; acute heart failure; heart failure; sodium glucose co-transporter 2 inhibitor
    DOI:  https://doi.org/10.1080/14796678.2025.2499374
  9. Medicine (Baltimore). 2025 May 02. 104(18): e42196
    Meta-analysis of the efficacy and safety of SGLT-2 inhibitors in patients with heart failure and type 2 diabetes mellitus.
    Xinliang Yao, Han Zhang, Xueli Lu.
       BACKGROUND: To investigate the efficacy and safety of sodium-glucose cotransporter 2 (SGLT-2) inhibitors in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM).
    METHODS: A manual search was conducted in 3 prestigious English databases, Cochrane Library, PubMed, and Web of Science, for studies published within the last decade, from July 2014 to July 2024. The extracted literature was synthesized to analyze the efficacy outcomes, survival prognostic indicators, and safety profiles of SGLT-2 inhibitors in patients with HF and T2DM. The Cochrane bias risk assessment scale was used as a tool to evaluate the quality of the literature, and Review Manager 5.4 software was used to create the bias risk chart. Data analysis and merging were completed with the help of Review Manager 5.4 and Stata 15.0 statistical software.
    RESULTS: Twelve studies encompassing 9509 patients were included in the meta-analysis. The results revealed that compared to the control group, the SGLT-2 inhibitor-treated group demonstrated significantly greater reductions in left ventricular end-diastolic volume index [mean difference (MD) = -7.25, 95% confidence intervals [95% CI] (-9.83, -4.67)], brain natriuretic peptide levels [MD = -36.96, 95% CI (-63.51, -10.41)], and N-terminal pro-brain natriuretic peptide [MD = -519.27, 95% CI (-660.77, -377.78)]. Furthermore, the SGLT-2 inhibitor-treated group exhibited significantly higher increases in Kansas City Cardiomyopathy Questionnaire scores [MD = 3.32, 95% CI (3.30, 3.34)], indicating improved quality of life. Additionally, the incidence of adverse events was significantly lower in the SGLT-2 inhibitor-treated group compared to the control group [OR = 0.78, 95% CI (0.69, 0.88)]. The pooled results of the meta-analysis indicated that SGLT-2 inhibitor therapy reduced the risk of cardiovascular death or HF hospitalization by 23%, the risk of cardiovascular death by 19%, and the risk of all-cause mortality by 9%.
    CONCLUSION: SGLT-2 inhibitor therapy significantly reduced the risks of all-cause mortality, cardiovascular death, and hospitalization for HF in patients with HF and T2DM. Additionally, SGLT-2 inhibitors significantly improve cardiac function, decrease the incidence of adverse events, and enhance the quality of life in these patients.
    Keywords:  SGLT-2 inhibitors; efficacy and safety; heart failure; meta-analysis; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1097/MD.0000000000042196
  10. Circ Res. 2025 May 09.
    Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF.
    Mark E Pepin, Philipp J M Konrad, Sumra Nazir, Farhad Bazgir, Christoph Maack, Alexander Nickel, Joshua Gorman, Mathias Hohl, Friederike Schreiter, Matthias Dewenter, Adriano de Britto Chaves Filho, Almut Schulze, Anja Karlstaedt, Norbert Frey, Christine Seidman, Jonathan Seidman, Johannes Backs.
       BACKGROUND: Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes ad libitum high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester, we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester.
    METHODS: Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein Nnt (nicotinamide nucleotide transhydrogenase), we used an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt-/-) Nnt in the C57BL/6N background were challenged with high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester for 9 weeks (n=6-10).
    RESULTS: Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via E/e' (42.8 versus 21.5, P=1.2×10-10), E/A (2.3 versus 1.4, P=4.1×10-2), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, P=5.1×10-3), and myocardial fibrosis (P=2.3×10-2). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD+ (P=8.4×10-3) and a 38.8% reduction in glutathione:GSSG (P=2.6×10-2) among Nnt+/+ mice after high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling of myocardial fibrosis.
    CONCLUSIONS: Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.
    Keywords:  NG-nitroarginine methyl ester; fibrosis; genetic therapy; heart failure; oxidative stress
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326154
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