bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2025–04–20
six papers selected by
Kyle McCommis, Saint Louis University
  1. Plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fraction.
  2. The ketone body 3-hydroxybutyrate increases cardiac output and cardiac contractility in a porcine model of cardiogenic shock: a randomized, blinded, crossover trial.
  3. Impaired cardiac branched-chain amino acid metabolism in a novel model of diabetic cardiomyopathy.
  4. Direct Cardiac Mechanisms of the Sodium Glucose Co-Transporter 2 Inhibitor Class.
  5. Physical activity of moderate-intensity optimizes myocardial citrate cycle in a murine model of heart failure.
  6. Crossover Trial of Exogenous Ketones on Cardiometabolic Endpoints in Heart Failure With Preserved Ejection Fraction.
  1. ESC Heart Fail. 2025 Apr 15.
    Plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fraction.
    Fawaz Naeem, Teresa C Leone, Christopher Petucci, Clarissa Shoffler, Ravindra C Kodihalli, Tiffany Hidalgo, Cheryl Tow-Keogh, Jessica Mancuso, Iphigenia Tzameli, Donald Bennett, John D Groarke, Rachel J Roth Flach, Daniel J Rader, Daniel P Kelly.
       AIMS: Two general phenotypes of heart failure (HF) are recognized: HF with reduced ejection fraction (HFrEF) and with preserved EF (HFpEF). To develop phenotype-specific approaches to treatment, distinguishing biomarkers are needed. The goal of this study was to utilize quantitative metabolomics on a large, diverse population to replicate and extend existing knowledge of the plasma metabolic signatures in human HF.
    METHODS: Plasma metabolomics and proteomics was conducted on 787 samples collected by the Penn Medicine BioBank from subjects with HFrEF (n = 219), HFpEF (n = 357) and matched controls (n = 211). A total of 90 metabolites were analysed, comprising 28 amino acids, 8 organic acids and 54 acylcarnitines. Seven hundred thirty-three of these samples also underwent proteomic profiling via the O-Link proteomics panel.
    RESULTS: Unsaturated forms of medium-/long-chain acylcarnitines were elevated in the HFrEF group. Amino acid derivatives, including 1- and 3-methylhistidine, homocitrulline and symmetric and asymmetric (ADMA) dimethylarginine were elevated in HF, with ADMA elevated uniquely in HFpEF. While the branched-chain amino acids (BCAAs) were minimally changed, short-chain acylcarnitine species indicative of BCAA catabolism were elevated in both HF groups. 3-hydroxybutyrate (3-HBA) and its metabolite, C4-OH carnitine, were uniquely elevated in the HFrEF group. Linear regression models demonstrated a significant correlation between plasma 3-HBA and N-terminal pro-brain natriuretic peptide in both forms of HF, stronger in HFrEF.
    CONCLUSIONS: These results identify plasma signatures that are shared as well as potentially distinguish HFrEF and HFpEF. Metabolite markers for ketogenic metabolic re-programming were identified as unique signatures in the HFrEF group, possibly related to increased levels of BNP. Our results set the stage for future studies aimed at assessing selected metabolites as relevant biomarkers to guide HF phenotype-specific therapeutics.
    Keywords:  biomarkers; cardiac energetics; heart failure; ketone bodies; lipid metabolism; metabolomics
    DOI:  https://doi.org/10.1002/ehf2.15285
  2. Basic Res Cardiol. 2025 Apr 12.
    The ketone body 3-hydroxybutyrate increases cardiac output and cardiac contractility in a porcine model of cardiogenic shock: a randomized, blinded, crossover trial.
    Oskar Kjærgaard Hørsdal, Alexander Møller Larsen, Kasper Lykke Wethelund, Frederik Flyvholm Dalsgaard, Jacob Marthinsen Seefeldt, Ole Kristian Lerche Helgestad, Niels Moeslund, Jacob Eifer Møller, Hanne Berg Ravn, Roni Ranghøj Nielsen, Henrik Wiggers, Kristoffer Berg-Hansen, Nigopan Gopalasingam.
      Cardiogenic shock (CS) is characterized by reduced cardiac output (CO), reduced end-organ perfusion, and high mortality. Medical therapies have failed to improve survival. The ketone body 3-hydroxybutyrate (3-OHB) enhances cardiac function in heart failure and CS. We aimed to elucidate the cardiovascular and cardiometabolic effects of 3-OHB treatment during CS. In a randomized, assessor-blinded crossover design, we studied 16 female pigs (60 kg, 5 months of age). CS was induced by left main coronary artery microsphere injections. Predefined criteria for CS were a 30% reduction in CO or mixed venous saturation (SvO2). Intravenous 3-OHB infusion and a matching control solution were administered for 120 min in random order. Hemodynamic measurements were obtained by pulmonary artery catheterization and a left ventricular (LV) pressure-volume catheter. Myocardial mitochondrial function was assessed using high resolution respirometry. During CS, infusion with 3-OHB increased CO by 0.9 L/min (95%CI 0.4-1.3 L/min) compared with control infusion. SvO2 (P = 0.026) and heart rate (P < 0.001) increased. Stroke volume (P = 0.6) was not altered. LV contractile function as determined by LV end-systolic elastance improved during 3-OHB infusion compared with control infusion (P = 0.004). Systemic and pulmonary vascular resistance decreased, and diuresis increased. LV mitochondrial function was higher after 3-OHB infusion compared with control. We conclude that 3-OHB infusion enhances cardiac function by increasing contractility and reducing vascular resistance, while also preserving myocardial mitochondrial respiratory function in a large animal model of ischemic CS. These novel findings support the therapeutic potential of exogenous ketone supplementation in CS management.
    Keywords:  3-Hydroxy butyrate; Cardiac output; Cardiogenic shock; Cardiometabolic; Hemodynamics; Mitochondrial function
    DOI:  https://doi.org/10.1007/s00395-025-01103-2
  3. Cardiovasc Diabetol. 2025 Apr 16. 24(1): 167
    Impaired cardiac branched-chain amino acid metabolism in a novel model of diabetic cardiomyopathy.
    Junko Asakura, Manabu Nagao, Masakazu Shinohara, Tetsuya Hosooka, Naoya Kuwahara, Makoto Nishimori, Hidekazu Tanaka, Seimi Satomi-Kobayashi, Sho Matsui, Tsutomu Sasaki, Tadahiro Kitamura, Hiromasa Otake, Tatsuro Ishida, Wataru Ogawa, Ken-Ichi Hirata, Ryuji Toh.
       BACKGROUND: Systemic insulin resistance plays an important role in the pathogenesis of type 2 diabetes and its complications. Although impaired branched-chain amino acid (BCAA) metabolism has been reported to be involved in the development of diabetes, the relationship between cardiac BCAA metabolism and the pathogenesis of diabetic cardiomyopathy (DbCM) remains unclear.
    OBJECTIVES: The aim of this study was to investigate BCAA metabolism in insulin-resistant hearts by using a novel mouse model of DbCM.
    METHODS: The cardiac phenotypes of adipocyte-specific 3'-phosphoinositide-dependent kinase 1 (PDK1)-deficient (A-PDK1KO) mice were assessed by histological analysis and echocardiography. The metabolic characteristics and cardiac gene expression were determined by mass spectrometry or RNA sequencing, respectively. Cardiac protein expression was evaluated by Western blot analysis.
    RESULTS: A-PDK1KO mouse hearts exhibited hypertrophy with prominent insulin resistance, consistent with cardiac phenotypes and metabolic disturbances previously reported as DbCM characteristics. RNA sequencing revealed the activation of BCAA uptake in diabetic hearts. In addition, the key enzymes involved in cardiac BCAA catabolism were downregulated at the protein level in A-PDK1KO mice, leading to the accumulation of BCAAs in the heart. Mechanistically, the accumulation of the BCAA leucine caused cardiac hypertrophy via the activation of mammalian target of rapamycin complex 1 (mTORC1).
    CONCLUSIONS: A-PDK1KO mice closely mimic the cardiac phenotypes and metabolic alterations observed in human DbCM and exhibit impaired BCAA metabolism in the heart. This model may contribute to a better understanding of DbCM pathophysiology and to the development of novel therapies for this disease.
    Keywords:  Branched-chain amino acid; Cardiac metabolism; Diabetes mellitus; Diabetic cardiomyopathy; Heart failure
    DOI:  https://doi.org/10.1186/s12933-025-02725-5
  4. J Cardiovasc Pharmacol Ther. 2025 Jan-Dec;30:30 10742484251323428
    Direct Cardiac Mechanisms of the Sodium Glucose Co-Transporter 2 Inhibitor Class.
    Steven Hopkins, Faiz Baqai, Saivaroon Gajagowni, Gavin Hickey.
      BackgroundSodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated significant cardiovascular benefits in clinical trial. While their role in reducing heart failure hospitalizations and cardiovascular mortality is well established, the precise mechanisms underlying their direct cardiac effects remain unclear. This literature review aims to synthesize current knowledge on the molecular and physiological pathways by which SGLT2 inhibitors may exert effects on cardiac tissue, independent of glycemic control.MethodsA comprehensive review of peer-reviewed articles, randomized controlled trials, meta-analyses, and mechanistic studies published in PubMed and related databases was conducted. The search focused on studies examining the direct impact of SGLT2 inhibitors on cardiac function, remodeling, metabolism, and intracellular signaling pathways. Only studies evaluating the cardiac effects separate from their glucose-lowering action were included in the analysis.ResultsThis review identified several key mechanisms by which SGLT2 inhibitors may benefit the heart directly, including reductions in oxidative stress, inflammation, and myocardial fibrosis. Emerging evidence suggests that these drugs modulate key pathways such as sodium-hydrogen exchange (NHE) inhibition, improvement of mitochondrial function, and promotion of ketone body utilization in cardiomyocytes.ConclusionsSGLT2 inhibitors appear to confer direct cardioprotective effects. These include anti-inflammatory, anti-fibrotic, and energy efficiency improvements in the myocardium. The findings highlight new potential therapeutic mechanisms and provide a foundation for further research into the non-diabetic use of SGLT2 inhibitors in heart failure and other cardiac conditions. Understanding these direct effects could lead to optimized treatment strategies for patients with and without diabetes.
    Keywords:  NHE-1; SGLT2i; cardio fibroblasts; cardiomyocytes; glucosuria
    DOI:  https://doi.org/10.1177/10742484251323428
  5. Front Physiol. 2025 ;16 1568060
    Physical activity of moderate-intensity optimizes myocardial citrate cycle in a murine model of heart failure.
    Lucyna Widacha, Joanna Szramel, Zenon Nieckarz, Anna Kurpinska, Ryszard T Smolenski, Stefan Chlopicki, Jerzy A Zoladz, Joanna Majerczak.
       Introduction: There is growing body of evidence that an enhanced concentration of branched-chain amino acids (BCAAs), as a consequence of an impaired myocardial oxidative metabolism, is involved in the occurrence and progression of heart failure (HF). The purpose of this study was to examine the effect of 8 weeks of spontaneous wheel running (8-sWR) (reflecting low-to-moderate intensity physical activity) on the myocardial [BCAAs] and mitochondrial oxidative metabolism markers, such as tricarboxylic acid (TCA) cycle intermediates (TCAi), mitochondrial electron transport chain (ETC) proteins and mitochondrial DNA copy number (mtDNA/nDNA) in a murine model of HF.
    Methods: Adult heart failure (Tgαq*44) and wild-type (WT) mice were randomly assigned to either the sedentary or exercising group. Myocardial concentrations of [TCAi] and [BCAAs] were measured by LC-MS/MS, ETC proteins were determined by Western immunoblotting and mtDNA/nDNA was assessed by qPCR.
    Results: Heart failure mice exhibited decreased exercise performance capacity as reflected by a lower total distance covered and time of running in wheels. This was accompanied by impaired TCA cycle, including higher citrate concentration and greater [BCAAs] in the heart of Tgαq*44 mice compared to their control counterparts. No impact of disease at its current stage i.e., in the transition phase from the compensated to decompensated stage of HF on the myocardial mitochondrial ETC, proteins content was observed, however the altered basal level of mitochondrial biogenesis (lower mtDNA/nDNA) in the heart of Tgαq*44 mice compared to their control counterparts was detected. Interestingly, 8-sWR significantly decreased myocardial citrate content in the presence of unchanged myocardial [BCAAs], ETC proteins content and mtDNA copy number.
    Conclusion: Moderate-intensity physical activity, even of short duration, could be considered an effective intervention in heart failure. Our results suggest that central metabolic pathway - TCA cycle appears to be more sensitive to moderate-intensity physical activity (as reflected by the lowering of myocardial citrate concentration) than the mechanism(s) regulating the BCAAs turnover in the heart. This observation may have a particular importance in heart failure, since an improvement of impaired myocardial oxidative metabolism may contribute to the upgrading of the clinical status of patients.
    Keywords:  branched-chain amino acids; citrate; exercise tolerance; oxidative metabolism; tricarboxylic acid cycle intermediates
    DOI:  https://doi.org/10.3389/fphys.2025.1568060
  6. JACC Heart Fail. 2025 Mar 29. pii: S2213-1779(25)00237-9. [Epub ahead of print]
    Crossover Trial of Exogenous Ketones on Cardiometabolic Endpoints in Heart Failure With Preserved Ejection Fraction.
    Senthil Selvaraj, Antoneta Karaj, Julio A Chirinos, Nicole Denney, Gabby Grosso, Melissa Fernando, Kishon Chambers, Cassandra Demastus, Ravinder Reddy, Michael Langham, Dushyant Kumar, Hannah Maynard, Bianca Pourmussa, Stuart B Prenner, Jordana B Cohen, Harry Ischiropoulos, Michael R Rickels, David C Poole, David D Church, Robert R Wolfe, Daniel P Kelly, Mary Putt, Kenneth B Margulies, Payman Zamani.
       BACKGROUND: The etiology of exercise intolerance in heart failure with preserved ejection fraction (HFpEF) is multifactorial. Several contributing pathways may be improved by ketone ester (KE).
    OBJECTIVES: This study aims to determine whether KE improves exercise tolerance in HFpEF.
    METHODS: KETO-HFpEF (Ketogenic Exogenous Therapies in HFpEF) is a randomized, crossover, placebo-controlled trial of acute KE dosing in 20 symptomatic HFpEF participants. Coprimary endpoints include peak oxygen consumption (VO2) during incremental cardiopulmonary exercise testing and time to exhaustion during an additional constant-intensity exercise (75% peak workload) bout.
    RESULTS: The average age was 71 ± 8 years, 60% were women, and 65% were White. KE did not improve peak VO2 (KE: 10.4 ± 3.6 vs placebo: 10.5 ± 4.0 mL/kg/min; P = 0.75). At rest, heart rate, biventricular systolic function, and cardiac output (0.6 L/min [95% CI: 0.3-1.0 L/min]) were greater with KE vs placebo, whereas total peripheral resistance (-3.2 WU [95% CI: -5.2 to -1.2 WU]) and the arteriovenous oxygen content difference (-0.7 mL of O2/dL blood [95% CI: -1.2 to -0.2 mL]) were lower. These differences mostly disappeared during incremental exercise. KE did not improve exercise endurance during the constant-intensity protocol (9.7 ± 7.3 minutes vs 8.7 ± 4.4 minutes; P = 0.51). In 6 participants receiving 6,6-2H2-glucose infusions during constant-intensity exercise, plasma glucose appearance rate before and during exercise was lower with KE (-0.24 mg/kg/min; P < 0.001). During both exercise protocols, KE lowered: 1) respiratory exchange ratios, demonstrating decreased systemic carbohydrate use; 2) nonesterified fatty acids and glucose; and 3) estimated left ventricular filling pressures (E/e').
    CONCLUSIONS: Despite robust ketosis, shifting substrate use away from carbohydrates, and decreasing estimated left ventricular filling pressures, acute KE supplementation did not improve peak VO2 or constant-intensity exercise in HFpEF. (Ketogenic Exogenous Therapies in HFpEF [KETO-HFpEF]; NCT04633460).
    Keywords:  echocardiography; exercise; heart failure with preserved ejection fraction; ketones; metabolism; skeletal muscle; vascular stiffness
    DOI:  https://doi.org/10.1016/j.jchf.2025.03.002
This page is being maintained by Thomas Krichel. It was last updated on 2025‒04‒21 at 14:02.