bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2025–08–03
four papers selected by
Kyle McCommis, Saint Louis University



  1. Biomolecules. 2025 Jun 22. pii: 916. [Epub ahead of print]15(7):
      Diabetes mellitus (DM) is a complex global pandemic that frequently leads to multiple complications. Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with type 1 and 2 diabetes and is fundamentally characterized by abnormalities in myocardial structure and function. Metabolic disorders occupy a leading role in the pathogenesis of DCM, manifesting as disrupted substrate metabolism, dysregulated signaling pathways, and energy imbalance. Given the limited benefits of conventional therapeutic strategies targeting glucolipid metabolism, increasing research efforts have focused on amino acid metabolism. Amino acids are involved in the synthesis of nitrogen-containing compounds and serve as an energy source under specific conditions. Moreover, emerging studies demonstrate that metabolic disturbances of specific amino acids-such as branched-chain amino acids (BCAAs), glutamine, and arginine-exacerbate mitochondrial dysfunction and oxidative stress, thereby promoting myocardial fibrosis and cardiomyocyte injury. Therefore, this review aims to summarize the general characteristics and regulatory pathways of amino acid metabolism, as well as the specific mechanisms by which metabolic alterations of amino acids contribute to the pathogenesis and progression of diabetic cardiomyopathy, with the hope of advancing more effective translational therapeutic approaches.
    Keywords:  amino acid metabolism; aromatic amino acid; branched-chain amino acid; diabetic cardiomyopathy
    DOI:  https://doi.org/10.3390/biom15070916
  2. J Am Heart Assoc. 2025 Jul 29. e041401
       BACKGROUND: Hypertrophic cardiomyopathy (HCM), characterized by ventricular hypertrophy and fibrosis, frequently progresses to heart failure. Although metabolic dysregulation is implicated in HCM pathophysiology, the role of PDK4 (pyruvate dehydrogenase kinase 4), a key regulator of cardiac glucose and fatty acid oxidation, in HCM-related heart failure remains unknown.
    METHODS: Single-nucleus RNA sequencing was performed to analyze gene expression in patients with HCM (n=12), categorized into the following groups: normal, reduced, and heart failure. We validated our findings in additional cohorts of patients undergoing septal resection or heart transplantation. Cardiac-specific Pdk4 knockout mice were crossed with Mybpc3 knockout mice, and PDK4 inhibition was also tested in Mybpc3 knockout mice. Cardiac metabolism was assessed via metabolic flux and Seahorse analysis in vivo and in vitro.
    RESULTS: Single-nucleus RNA sequencing identified distinct cardiomyocyte clusters, with cardiomyocyte cluster 4 (PDK4+ cardiomyocytes) significantly associated with impaired cardiac function and highly expressed in the cardiac tissue of patients with HCM heart failure. Elevated PDK4 inhibited pyruvate conversion to acetyl-coenzyme A, impairing tricarboxylic acid cycle flux and reducing glucose oxidation, as confirmed by metabolic tracking. Both genetic ablation and pharmacological inhibition of PDK4 attenuated heart failure symptoms in Mybpc3 knockout mice.
    CONCLUSIONS: Our findings highlight metabolic disturbance, specifically PDK4-driven suppression of glucose oxidation, as crucial in HCM progression to heart failure. PDK4 represents a promising therapeutic target for preventing or treating heart failure in patients with HCM.
    Keywords:  cardiac hypertrophy; heart failure; hypertrophic cardiomyopathy; pyruvate metabolism
    DOI:  https://doi.org/10.1161/JAHA.125.041401
  3. JACC Adv. 2025 Jul 24. pii: S2772-963X(25)00440-5. [Epub ahead of print]4(8): 102016
       BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have cardioprotective effects without acting directly on the myocardium.
    OBJECTIVES: The purpose of the study was to evaluate the impact of SGLT2i on myocardial glucose utilization.
    METHODS: This retrospective propensity-matched cohort study examined subjects who underwent whole-body 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography for oncologic purposes between 2016 and 2024. A 1:1 propensity match analyzed positron emission tomography-derived myocardial FDG uptake, maximum myocardial standardized uptake value (SUV), and total myocardial glycolysis in SGLT2i-treated vs untreated patients.
    RESULTS: Among 6,747 subjects, 187 were actively prescribed SGLT2i and matched with 187 who were not. Mean age was 68.4 ± 9.7 years, 57.5% were males, 81.8% had diabetes, and 41.4% had heart failure. Myocardial FDG uptake (to quantify glucose utilization) was absent in 64.7% of patients on SGLT2i and 37.4% not on SGLT2i (P < 0.001), despite higher prescan glucose in those receiving SGLT2i (124 vs 110 mg/dL). SUVmax (5.4 vs 5.8, P = 0.004), volume of myocardial FDG uptake (0.8 cm3 vs 4.6 cm3, P = 0.001), and total myocardial glycolysis (1.6 g vs 20.6 g, P < 0.001) were significantly lower in patients treated with SGLT2i vs those untreated. SGLT2i use blunted insulin-induced increases in total myocardial glycolysis (P-interaction 0.036). There was no difference in background SUVmax and SUVmean in the blood pool and liver.
    CONCLUSIONS: SGLT2i use was associated with a greater suppression of myocardial glucose without affecting background tissue glycolysis despite higher prescan glucose levels. These findings add to the understanding of the effect of SGLT2i on the myocardium and may have implications with respect to cardiac imaging protocols that require glucose manipulation.
    Keywords:  cardiomyopathy; diabetes; fatty acids; heart failure; ketone body; metabolic syndrome
    DOI:  https://doi.org/10.1016/j.jacadv.2025.102016
  4. Open Med (Wars). 2025 ;20(1): 20251210
       Background: Heart failure remains a major public health issue, and there are still no reliable biomarkers for left ventricular ejection fraction (LVEF).
    Objective: To screen for differential metabolites in the blood of HFpEF, HFmrEF, and HFrEF patients based on metabolomics analysis of their blood samples.
    Methods: Total 44 patients in HFpEF group, 30 patients in HFmrEF group, and 36 patients in HFrEF group were selected. The blood metabolites were analyzed by liquid chromatography high-resolution mass spectrometry and classified by principal component analysis, and then potential biomarker were screened. Partial least squares discriminant analysis was used to model and investigate the predictive ability of biomarkers for LVEF.
    Results: Blood metabolite profiles of HFpEF, HFmrEF, and HFrEF groups could be well distinguished, and seven potential biomarkers were identified, such as phosphatidylcholine, phosphatidylinositol, lysophosphatidylcholine, lysophosphatidylcholine, ceramide, sphingosine, and sphingomyelin. Four metabolic pathways, such as glycerol phospholipid metabolic pathway, linoleic acid metabolic pathway, purine pyrimidine metabolism pathway, and linolenic acid metabolism pathway were identified, among which glycerol phospholipid metabolism pathway was the most significant.
    Conclusion: The changes in glycerol phospholipid metabolism pathway may help identify HFpEF, HFmrEF, and HFrEF.
    Keywords:  LVEF; glycerophospholipid metabolic pathway; heart failure; liquid phase high-resolution mass spectrometry; metabolome
    DOI:  https://doi.org/10.1515/med-2025-1210