bims-hafaim 2025-02-23 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–02–23
nine papers selected by
Kyle McCommis, Saint Louis University

Myocardial metabolic flexibility following ketone infusion demonstrated by hyperpolarized [2-13C]pyruvate MRS in pigs.
SGLT2i Therapy Prevents Anthracycline-Induced Cardiotoxicity in a Large Animal Model by Preserving Myocardial Energetics.
Ultrastructure analysis of mitochondria, lipid droplet and sarcoplasmic reticulum apposition in human heart failure.
Empagliflozin to Prevent Doxorubicin Cardiotoxicity.
FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice.
Cardiomyocyte-specific deletion of STING improves cardiac function, glucose homeostasis, and wound healing in diabetic mice.
Sodium Glucose Cotransporter 2 inhibitors in Patients with Amyloidosis With or Without Heart Failure.
Genes of the Fatty Acid Oxidation Pathway are Upregulated in Female as Compared to Male Cardiomyocytes.
Partial Regulation of Ketone Metabolism by Hypoxia in H9C2 Cardiomyocytes.

Sci Rep. 2025 Feb 18. 15(1): 5849

Myocardial metabolic flexibility following ketone infusion demonstrated by hyperpolarized [2-13C]pyruvate MRS in pigs.

Sabrina Kahina Bech, Esben Søvsø Szocska Hansen, Bent Roni Nielsen, Henrik Wiggers, Mads Bisgaard Bengtsen, Christoffer Laustsen, Jack J Miller.

This study aims to investigate the effects of β-3-hydroxybutyrate (β-3-OHB) infusion on myocardial metabolic flexibility using hyperpolarized [2-13C]pyruvate magnetic resonance spectroscopy (MRS) in the pig heart. We hypothesized that β-3-OHB infusion will cause rapid, quantifiable alterations in tricarboxylic acid (TCA) cycle flux as measured non-invasively by 13C MRS and reflect myocardial work. Five female Danish landrace pigs underwent β-3-OHB infusion during a hyperinsulinemic euglycemic clamp (HEC). Cardiac metabolism and hemodynamics were monitored using hyperpolarized [2-13C]pyruvate MRS and cardiac MRI. β-3-OHB infusion during HEC resulted in significant increases in cardiac output over baseline (from 1.9 to 3.8 L/min, p = 0.0011) and heart rate (from 51 to 85 bpm, p = 0.0004). Metabolic analysis showed a shift towards increased lactate production and decreased levels of acetyl-carnitine and glutamate during β-3-OHB infusion. Following the termination of the infusion, a normalization of these metabolic markers was observed. These results demonstrate the profound metabolic adaptability of the myocardium to ketone body utilization. The infusion of Na-β-3-OHB significantly alters both the hemodynamics and metabolism of the porcine heart. The observed increase in cardiac output and metabolic shifts towards lactate production suggest that ketone bodies could potentially enhance cardiac function by providing an efficient-energy substrate that, if provided, is preferentially used. This study provides new insights into the metabolic flexibility of the heart and hints at the potential therapeutic benefits of ketone interventions in heart failure treatment.

DOI: https://doi.org/10.1038/s41598-025-90215-9
JACC CardioOncol. 2025 Feb;pii: S2666-0873(24)00447-2. [Epub ahead of print]7(2): 171-184

SGLT2i Therapy Prevents Anthracycline-Induced Cardiotoxicity in a Large Animal Model by Preserving Myocardial Energetics.

Danielle Medina-Hernández, Laura Cádiz, Annalaura Mastrangelo, Andrea Moreno-Arciniegas, Miguel Fernández Tocino, Alejandro A Cueto Becerra, Anabel Díaz-Guerra Priego, Warren A Skoza, María Isabel Higuero-Verdejo, Gonzalo Javier López-Martín, Claudia Pérez-Martínez, Antonio de Molina-Iracheta, María Caballero-Valderrama, Javier Sánchez-González, David Sancho, Valentin Fuster, Carlos Galán-Arriola, Borja Ibáñez.

   BACKGROUND: Anthracycline-induced cardiotoxicity (AIC) is characterized by a disruption in myocardial metabolism.
OBJECTIVES: The authors used a large animal model to test sodium-glucose cotransporter inhibitor therapy to prevent AIC.
METHODS: Female large white pigs (n = 36) were used to identify the most translational AIC regimen: 6 triweekly intravenous doxorubicin injections (1.8 mg/kg each). Another group of 32 pigs were randomized (1:1:2) to doxorubicin plus empagliflozin 20 mg, doxorubicin plus empagliflozin 10 mg, or doxorubicin control. Pigs were serially examined using multiparametric cardiac magnetic resonance and magnetic resonance spectroscopy. At the end of the 21-week follow-up period, blood samples were obtained to measure myocardial metabolic substrate extraction, and the left ventricle was harvested and processed for analysis using metabolomics, transmission electron microscopy, mitochondrial respirometry, and histopathology.
RESULTS: Final left ventricular ejection fraction (LVEF), the prespecified primary outcome, was significantly higher in pigs receiving 20 mg empagliflozin than in the doxorubicin control group (median 57.5% [Q1-Q3: 55.5%-60.3%] vs 47.0% [Q1-Q3: 40.8%-47.8%]; P = 0.027). Final LVEF in pigs receiving 10 mg empagliflozin was 51% (Q1-Q3: 46.5%-55.5%; P = 0.020 vs 20 mg empagliflozin). The incidence of AIC events was 0%, 50%, and 72% in the empagliflozin 20 mg, empagliflozin 10 mg, and doxorubicin control groups, respectively. Empagliflozin 20 mg treatment resulted in enhanced ketone body consumption by the myocardium, preserved magnetic resonance spectroscopy-measured cardiac energetics, and improved mitochondrial structure and function on transmission electron microscopy and respirometry. These changes were more modest with the 10-mg empagliflozin dose.
CONCLUSIONS: Sodium-glucose cotransporter-2 inhibitor therapy with empagliflozin exerts a dose-dependent cardioprotective effect against AIC. The improved LVEF was accompanied by enhanced ketone body consumption, improved cardiac energetics, and preserved mitochondrial structure and function.

Keywords:  anthracycline; cardio-oncology; cardiomyopathy; cardioprotection; doxorubicin cardiotoxicity; heart failure; imaging; ketosis; metabolism; myocardial energetics; pigs; sodium glucose contransporter-2 inhibitors; treatment

DOI:  https://doi.org/10.1016/j.jaccao.2024.12.004
bioRxiv. 2025 Jan 29. pii: 2025.01.29.635600. [Epub ahead of print]

Ultrastructure analysis of mitochondria, lipid droplet and sarcoplasmic reticulum apposition in human heart failure.

Nadina R Latchman, Tyler L Stevens, Kenneth C Bedi, Benjamin L Prosser, Kenneth B Margulies, John W Elrod.

Background: Cardiomyocyte structural remodeling is reported as a causal contributor to heart failure (HF) development and progression. Growing evidence highlights the role of organelle apposition in cardiomyocyte function and homeostasis. Disruptions in organelle crosstalk, such as that between the sarcoplasmic reticulum (SR) and mitochondria, are thought to impact numerous cellular processes such as calcium handling and cellular bioenergetics; two processes that are disrupted and implicated in cardiac pathophysiology. While the physical distance between organelles is thought to be essential for homeostatic cardiomyocyte function, whether the interactions and coupling of organelles are altered in human heart failure remains unclear.
Methods: Here, we utilized transmission electron microscopy and careful quantification of ultrastructure to characterize the changes in organelle apposition in cardiomyocytes isolated from the hearts of patients diagnosed with various types of HF. Subsequently we employed molecular approaches to examine the expression of proposed organelle tethers.
Results: We demonstrate that cardiomyocytes isolated from dilated cardiomyopathy, hypertrophic cardiomyopathy and ischemic cardiomyopathy hearts display smaller, more rounded mitochondria, as compared to nonfailing controls. Failing cardiomyocytes also exhibited disrupted SR-mitochondria juxtaposition and changes in the expression of proposed molecular tethers. Further analysis revealed alterations in lipid droplet dynamics including decreased lipid droplet content and less lipid droplets in association with mitochondria in failing cardiomyocytes.
Conclusion: Here we observed changes in organelle dynamics in cardiomyocytes isolated from heart failure patients diagnosed with differing etiologies. Our results suggest that organelle structure and apposition may be a ubiquitous contributor to human HF progression.
RESEARCH PERSPECTIVE: What is New? We provide a detailed analysis of organelle apposition in human heart failure, which has been understudied, and report that that failing human cardiomyocytes display an increase in distance between mitochondria and both the sarcoplasmic reticulum and lipid droplets.Structural changes in organelles are correlated with the expression of proposed organelle tethers.Resource of ultrastructural changes in organelle apposition in human heart failure resulting from various etiologies. What Questions Should be Addressed next? The results from this study provide rationale for causal experimentation to elucidate the contribution of organelle apposition to the progression of heart failure. Future studies examining mechanisms of mitochondrial tethering to the SR or lipid droplet will evaluate specific targets for therapeutic application.

DOI: https://doi.org/10.1101/2025.01.29.635600
JACC CardioOncol. 2025 Feb;pii: S2666-0873(25)00012-2. [Epub ahead of print]7(2): 185-187

Empagliflozin to Prevent Doxorubicin Cardiotoxicity.

Zhen Guo, Ali Javaheri.



Keywords:  anthracycline; cardio-oncology; cardiomyopathy; cardioprotection; doxorubicin cardiotoxicity; heart failure; imaging; ketosis; metabolism; myocardial energetics; pigs; sodium-glucose contransporter-2 inhibitors; treatment

DOI:  https://doi.org/10.1016/j.jaccao.2025.01.005
Nat Commun. 2025 Feb 15. 16(1): 1661

FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice.

Ke Zhang, Jing Gan, Baile Wang, Wei Lei, Dong Zhen, Jie Yang, Ningrui Wang, Congcong Wen, Xiaotang Gao, Xiaokun Li, Aimin Xu, Xinguang Liu, Yulin Li, Fan Wu, Zhuofeng Lin.

Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects, is beneficial for various cardiac disorders. However, FGF21's role in heart failure with preserved ejection fraction (HFpEF) remains unclear. Here, we show that elevated circulating FGF21 levels are negatively associated with cardiac diastolic function in patients with HFpEF. Global or adipose FGF21 deficiency exacerbates cardiac diastolic dysfunction and damage in high-fat diet (HFD) plus N[w]-nitro-L-arginine methyl ester (L-NAME)-induced HFpEF mice, whereas these effects are notably reversed by FGF21 replenishment. Mechanistically, FGF21 enhances the production of adiponectin (APN), which in turn indirectly acts on cardiomyocytes, or FGF21 directly targets cardiomyocytes, to negatively regulate pyruvate dehydrogenase kinase 4 (PDK4) production by activating PI3K/AKT signals, then promoting mitochondrial bioenergetics. Additionally, APN deletion strikingly abrogates FGF21's protective effects against HFpEF, while genetic PDK4 inactivation markedly mitigates HFpEF in mice. Thus, FGF21 protects against HFpEF via fine-tuning the multiorgan crosstalk among the adipose, liver, and heart.

DOI: https://doi.org/10.1038/s41467-025-56885-9
Life Sci. 2025 Feb 15. pii: S0024-3205(25)00103-1. [Epub ahead of print]366-367 123470

Cardiomyocyte-specific deletion of STING improves cardiac function, glucose homeostasis, and wound healing in diabetic mice.

Xiaorong Li, Kai Guo, Qingju Zhou, Felycia Fernanda Hosyanto, Guoxiang Zhou, Yiying Zhang, Yuanjing Li, Shenglan Yang.

   AIMS: The present study aimed to investigate the effects and underling mechanisms of cardiomyocyte-specific STING knockout on cardiac function and wound healing in diabetes.
MATERIALS AND METHODS: In this study, type 2 diabetes was induced in cardiomyocyte-specific STING knockout mice using a combination of a high-fat diet and streptozotocin. Cardiac function and remodeling were assessed by echocardiography and histopathological analysis. Glucose homeostasis was evaluated through insulin sensitivity tests and intraperitoneal glucose tolerance tests. Wound healing was quantified by measuring the wound area in diabetic mice.
KEY FINDINGS: The results demonstrated that STING deletion in cardiomyocytes improved cardiac function in diabetic mice, which was accompanied by enhanced insulin sensitivity and improved glucose tolerance. Furthermore, the deletion of STING partially mitigated mitochondrial dysfunction in the myocardium. STING knockout in cardiomyocytes also facilitated angiogenesis and wound healing in diabetic mice.
SIGNIFICANCE: Our findings suggest that cardiomyocyte-specific STING deletion enhances cardiac function, glucose homeostasis, and wound healing, indicating that targeting STING in the heart may serve as a promising therapeutic strategy for managing diabetes mellitus.

Keywords:  Diabetes; Diabetic cardiomyopathy; Glucose homeostasis; Wound healing

DOI:  https://doi.org/10.1016/j.lfs.2025.123470
Am J Med. 2025 Feb 15. pii: S0002-9343(25)00092-0. [Epub ahead of print]

Sodium Glucose Cotransporter 2 inhibitors in Patients with Amyloidosis With or Without Heart Failure.

Silvio N Augusto, Rochell Issa, Simon Vanhentenrijk, David Kaelber, W H Wilson Tang.

   BACKGROUND: Emerging evidence suggests sodium-glucose cotransporter 2 inhibitors (SGLT2i) benefits may extend to patients with amyloid cardiomyopathy, including transthyretin and amyloid light-chain amyloidosis subtypes. This study explores the broader implications of SGLT2i therapy across the spectrum of amyloidosis.
METHODS: This retrospective cohort study used de-identified electronic health records from the TriNetX platform, encompassing data from 101 healthcare organizations between 2009 and 2024. Two cohorts of amyloidosis patients with heart failure were compared based on SGLT2i use. One cohort without a diagnosis of heart failure was also tested. Propensity score matching was applied to balance baseline characteristics. The primary outcome was all-cause mortality, and secondary outcomes included acute heart failure, acute myocardial infarction, stroke, and chronic kidney disease.
RESULTS: The matched cohorts included 5,612 patients, with a mean age of 74 years and 64% male. SGLT2i-treated patients exhibited a higher 5-year survival probability (62.6%) compared to non-SGLT2i patients (39.1%) (HR 0.54, 95% CI 0.50-0.59; p<0.001). In amyloidosis patients without heart failure (n=1,490), SGLT2i therapy was associated with a significant reduction in all-cause mortality (HR 0.57, 95% CI 0.43-0.74; p <0.001). Sub-cohorts of transthyretin and amyloid light-chain amyloidosis in heart failure patients demonstrated consistent benefits with reduced mortality and favorable trends for acute myocardial infarction and stroke.
CONCLUSION: SGLT2i therapy is associated with significant survival benefits in amyloidosis patients with HF and may offer broader advantages across the amyloidosis spectrum, including amyloid patients without heart failure.

Keywords:  SGLT2 inhibitors; amyloid light-chain amyloidosis; amyloidosis; heart failure; transthyretin amyloidosis

DOI:  https://doi.org/10.1016/j.amjmed.2025.02.010
Circulation. 2025 Feb 18. 151(7): 511-514

Genes of the Fatty Acid Oxidation Pathway are Upregulated in Female as Compared to Male Cardiomyocytes.

Maya Talukdar, Lukáš Chmátal, Linyong Mao, Daniel Reichart, Danielle S Murashige, Helen Skaletsky, Daniel M DeLaughter, Zoltan Arany, Jonathan G Seidman, Christine E Seidman, David C Page.



Keywords:  metabolism; sex characteristics

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.071973
Curr Med Sci. 2025 Feb 20.

Partial Regulation of Ketone Metabolism by Hypoxia in H9C2 Cardiomyocytes.

Li-Zhen Chen, Hong-Qing Chen, Xin-Yuan Zhang, Shuang Ling, Jin-Wen Xu.

   OBJECTIVE: Hypoxia plays a critical role in the pathophysiology of cardiomyopathy, myocardial infarction, and heart failure. Promoting ketone metabolism has been shown to be beneficial for myocardial cells under hypoxic conditions. However, the expression and regulatory mechanisms of key enzymes in the ketone pathway under hypoxic conditions are still unclear. This study aimed to investigate the effects of hypoxia on the expression of key enzymes in the ketone metabolic pathway and the underlying regulatory mechanisms involved.
METHODS: H9C2 myocardial cells were cultured for 6 h in an oxygen-glucose-deprived state, and the expression of various genes was detected by quantitative real-time PCR. ELISA and lactate dehydrogenase (LDH) cytotoxicity assay were used to measure CoAs, itaconic acid, and LDH levels, respectively, and the dependence of gene expression on hypoxia-inducible factor-1 alpha (HIF-1α) was evaluated using the inhibitor LW6.
RESULTS: H9C2 cardiomyocytes exhibited increased ketone body metabolism in response to hypoxia. Hypoxia induced the expression of the ketone body enzymes succinyl-CoA:3-oxoacid CoA transferase (SCOT/OXCT1), 3-hydroxybutyrate dehydrogenase 2 (BDH2), and acyl-CoA: cholesterol acyltransferase 1 (ACAT1) in cardiomyocytes, with a concomitant increase in the level of acyl-CoA and a decrease in the level of succinyl-CoA. The HIF-1α inhibitor LW6 could partially reverse the expression of BDH2 and ACAT1, as well as the levels of succinyl-CoA. Interestingly, however, hypoxia-induced SCOT/OXCT1 expression was not regulated by the HIF-1α inhibitor. In addition, hypoxia promoted the expression of inflammatory factors.
CONCLUSION: These data confirm the critical role of ketone metabolism in myocardial hypoxia and help to elucidate the pathophysiology of cardiomyopathy, myocardial infarction and heart failure.

Keywords:  Cardiomyocyte; Gene expression; Hypoxia; Ketone metabolism; Succinyl-CoA

DOI:  https://doi.org/10.1007/s11596-025-00002-w