bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2024‒06‒16
seven papers selected by
Kyle McCommis, Saint Louis University
  1. Xinbao Pill ameliorates heart failure via regulating the SGLT1/AMPK/PPARα axis to improve myocardial fatty acid energy metabolism.
  2. Liraglutide alleviates experimental diabetic cardiomyopathy in a PDH dependent manner.
  3. Circulating beta-hydroxybutyrate levels in advanced heart failure with reduced ejection fraction: Determinants and prognostic impact.
  4. Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.
  5. The Relationship Between Insulin Resistance Indicated by Triglyceride and Glucose Index and Left Ventricular Hypertrophy and Decreased Left Ventricular Diastolic Function with Preserved Ejection Fraction.
  6. Empagliflozin in the treatment of heart failure.
  7. Liraglutide ameliorates TAC-induced cardiac hypertrophy and heart failure by upregulating expression level of ANP expression.
  1. Chin Med. 2024 Jun 11. 19(1): 82
    Xinbao Pill ameliorates heart failure via regulating the SGLT1/AMPK/PPARα axis to improve myocardial fatty acid energy metabolism.
    Linjie Pan, Zhanchi Xu, Min Wen, Minghui Li, Dongxin Lyu, Haiming Xiao, Zhuoming Li, Junhui Xiao, Yuanyuan Cheng, Heqing Huang.
      BACKGROUND: Heart failure (HF) is characterized by a disorder of cardiomyocyte energy metabolism. Xinbao Pill (XBW), a traditional Chinese medicine formulation integrating "Liushen Pill" and "Shenfu Decoction," has been approved by China Food and Drug Administration for the treatment of HF for many years. The present study reveals a novel mechanism of XBW in HF through modulation of cardiac energy metabolism.METHODS: In vivo, XBW (60, 90, 120 mg/kg/d) and fenofibrate (100 mg/kg/d) were treated for six weeks in Sprague-Dawley rats that were stimulated by isoproterenol to induce HF. Cardiac function parameters were measured by echocardiography, and cardiac pathological changes were assessed using H&E, Masson, and WGA staining. In vitro, primary cultured neonatal rat cardiomyocytes (NRCMs) were induced by isoproterenol to investigate the effects of XBW on myocardial cell damage, mitochondrial function and fatty acid energy metabolism. The involvement of the SGLT1/AMPK/PPARα signalling axis was investigated.
    RESULTS: In both in vitro and in vivo models of ISO-induced HF, XBW significantly ameliorated cardiac hypertrophy cardiac fibrosis, and improved cardiac function. Significantly, XBW improved cardiac fatty acid metabolism and mitigated mitochondrial damage. Mechanistically, XBW effectively suppressed the expression of SGLT1 protein while upregulating the phosphorylation level of AMPK, ultimately facilitating the nuclear translocation of PPARα and enhancing its transcriptional activity. Knockdown of SGLT1 further enhanced cardiac energy metabolism by XBW, while overexpression of SGLT1 reversed the cardio-protective effect of XBW, highlighting that SGLT1 is probably a critical target of XBW in the regulation of cardiac fatty acid metabolism.
    CONCLUSIONS: XBW improves cardiac fatty acid energy metabolism to alleviate HF via SGLT1/AMPK/PPARα signalling axis.
    Keywords:  AMPK/PPARα axis; Heart failure; Myocardial energy metabolism; SGLT1; Xinbao Pill
    DOI:  https://doi.org/10.1186/s13020-024-00959-1
  2. J Endocrinol. 2024 Jun 01. pii: JOE-24-0032. [Epub ahead of print]
    Liraglutide alleviates experimental diabetic cardiomyopathy in a PDH dependent manner.
    Jordan Sf Chan, Amanda A Greenwell, Christina T Saed, Magnus J Stenlund, Indiresh A Mangra-Bala, Seyed Amirhossein Tabatabaei Dakhilli, Kunyan Yang, Sally R Ferrari, Farah Eaton, Keshav Gopal, John R Ussher.
      Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist used for the treatment of T2D, has been shown to alleviate diabetic cardiomyopathy (DbCM) in experimental T2D, which was associated with increased myocardial glucose oxidation. To determine whether this increase in glucose oxidation is necessary for cardioprotection, we hypothesized that liraglutide's ability to alleviate DbCM would be abolished in mice with cardiomyocyte-specific deletion of pyruvate dehydrogenase (PDH; Pdha1CM-/- mice), the rate-limiting-enzyme of glucose oxidation. Male Pdha1CM-/- mice and their myosin heavy chain-α Cre expressing littermates (αMHCCre mice) were subjected to experimental T2D via 10-weeks of high-fat diet supplementation, with a single low-dose injection of streptozotocin (75 mg/kg) provided at week-4. All mice were randomized to treatment with either vehicle control (VC) or liraglutide (30 μg/kg) twice daily during the final 2.5-weeks, with cardiac function assessed via ultrasound echocardiography. As expected, liraglutide treatment improved glucose homeostasis in both αMHCCre and Pdha1CM-/- mice with T2D, in the absence of weight loss. Parameters of systolic function were unaffected by liraglutide treatment in both αMHCCre and Pdha1CM-/- mice with T2D. However, liraglutide treatment alleviated diastolic dysfunction in αMHCCre mice, as indicated by an increase and decrease in the e'/a' and E/e' ratios, respectively. Conversely, liraglutide failed to rescue these indices of diastolic dysfunction in Pdha1CM-/- mice. Our findings suggest that increases in glucose oxidation are necessary for GLP-1R agonist mediated alleviation of DbCM. As such, strategies aimed at increasing PDH activity may represent a novel approach for the treatment of DbCM.
    DOI:  https://doi.org/10.1530/JOE-24-0032
  3. Eur J Heart Fail. 2024 Jun 10.
    Circulating beta-hydroxybutyrate levels in advanced heart failure with reduced ejection fraction: Determinants and prognostic impact.
    Luca Monzo, Jan Kovar, Barry A Borlaug, Jan Benes, Martin Kotrc, Katerina Kroupova, Antonin Jabor, Janka Franekova, Vojtech Melenovsky.
      AIMS: Patients with heart failure (HF) display metabolic alterations, including heightened ketogenesis, resulting in increased beta-hydroxybutyrate (β-OHB) formation. We aimed to investigate the determinants and prognostic impact of circulating β-OHB levels in patients with advanced HF and reduced ejection fraction (HFrEF).METHODS AND RESULTS: A total of 867 patients with advanced HFrEF (age 57 ± 11 years, 83% male, 45% diabetic, 60% New York Heart Association class III), underwent clinical and echocardiographic examination, circulating metabolite assessment, and right heart catheterization (n = 383). The median β-OHB level was 64 (interquartile range [IQR] 33-161) μmol/L (normal 0-74 μmol/L). β-OHB levels correlated with increased markers of lipolysis (free fatty acids [FFA]), higher natriuretic peptides, worse pulmonary haemodynamics, and lower humoral regulators of ketogenesis (insulin/glucagon ratio). During a median follow-up of 1126 (IQR 410-1781) days, there were 512 composite events, including 324 deaths, 81 left ventricular assist device implantations and 107 urgent cardiac transplantations. In univariable Cox regression, increased β-OHB levels (T3 vs. T1: hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.13-1.72, p = 0.002) and elevated FFA levels (T3 vs. T1: HR 1.39, 95% CI 1.09-1.79, p = 0.008) were both predictors of a worse prognosis. In multivariable Cox analysis evaluating the simultaneous associations of FFA and β-OHB levels with outcomes, only FFA levels remained significantly associated with adverse outcomes.
    CONCLUSIONS: In patients with advanced HFrEF, increased plasma β-OHB correlate with FFA levels, worse right ventricular function, greater neurohormonal activation and other markers of HF severity. The association between plasma β-OHB and adverse outcomes is eliminated after accounting for FFA levels, suggesting that increased β-OHB is a consequence reflecting heightened lipolytic state, rather than a cause of worsening HF.
    Keywords:  Beta‐hydroxybutyrate; Cardiovascular disease; Free fatty acid; Heart failure; Ketone bodies; Prognosis
    DOI:  https://doi.org/10.1002/ejhf.3324
  4. Cell Mol Life Sci. 2024 Jun 10. 81(1): 254
    Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.
    Yingzhen Du, Jialei Li, Zhe Dai, Yuxin Chen, Yao Zhao, Xiaoman Liu, Tian Xia, Pingjun Zhu, Yijin Wang.
      The endogenous mitochondrial quality control (MQC) system serves to protect mitochondria against cellular stressors. Although mitochondrial dysfunction contributes to cardiac damage during many pathological conditions, the regulatory signals influencing MQC disruption during septic cardiomyopathy (SC) remain unclear. This study aimed to investigate the involvement of pyruvate kinase M2 (PKM2) and prohibitin 2 (PHB2) interaction followed by MQC impairment in the pathogenesis of SC. We utilized LPS-induced SC models in PKM2 transgenic (PKM2TG) mice, PHB2S91D-knockin mice, and PKM2-overexpressing HL-1 cardiomyocytes. After LPS-induced SC, cardiac PKM2 expression was significantly downregulated in wild-type mice, whereas PKM2 overexpression in vivo sustained heart function, suppressed myocardial inflammation, and attenuated cardiomyocyte death. PKM2 overexpression relieved sepsis-related mitochondrial damage via MQC normalization, evidenced by balanced mitochondrial fission/fusion, activated mitophagy, restored mitochondrial biogenesis, and inhibited mitochondrial unfolded protein response. Docking simulations, co-IP, and domain deletion mutant protein transfection experiments showed that PKM2 phosphorylates PHB2 at Ser91, preventing LPS-mediated PHB2 degradation. Additionally, the A domain of PKM2 and the PHB domain of PHB2 are required for PKM2-PHB2 binding and PHB2 phosphorylation. After LPS exposure, expression of a phosphorylation-defective PHB2S91A mutant negated the protective effects of PKM2 overexpression. Moreover, knockin mice expressing a phosphorylation-mimetic PHB2S91D mutant showed improved heart function, reduced inflammation, and preserved mitochondrial function following sepsis induction. Abundant PKM2 expression is a prerequisite to sustain PKM2-PHB2 interaction which is a key element for preservation of PHB2 phosphorylation and MQC, presenting novel interventive targets for the treatment of septic cardiomyopathy.
    Keywords:  MQC; Mitochondria; PHB2; PKM2; Septic cardiomyopathy
    DOI:  https://doi.org/10.1007/s00018-024-05253-9
  5. Diabetes Metab Syndr Obes. 2024 ;17 2259-2272
    The Relationship Between Insulin Resistance Indicated by Triglyceride and Glucose Index and Left Ventricular Hypertrophy and Decreased Left Ventricular Diastolic Function with Preserved Ejection Fraction.
    Chengzhang Yang, Weifang Liu, Zijia Tong, Fang Lei, Lijin Lin, Xuewei Huang, Xingyuan Zhang, Tao Sun, Gang Wu, Huajing Shan, Shaoze Chen, Hongliang Li.
      Aim: The evidence on the association between insulin resistance (IR) and the prevalence or incidence of cardiac dysfunction has been controversial, and the relationship between pre-diabetic IR and cardiac function is lacking. Large sample studies in the Chinese general population are urgently needed to explore the association between IR and the risk of left ventricular hypertrophy (LVH) and decreased left ventricular diastolic function with preserved ejection fraction (LVDFpEF).Methods: Based on a National Health Check-up database in China, we conducted a multicenter cross-sectional retrospective study in 344,420 individuals. Furthermore, at a single center, we performed two retrospective longitudinal studies encompassing 8270 and 5827 individuals to investigate the association between IR and the development of new-onset LVH and LVDFpEF, respectively. The median follow-up duration exceeded 2.5 years. The triglyceride and glucose (TyG) index, known for its high sensitivity in detecting IR, serves as a reliable alternative marker of IR. The logistic and cox proportional hazard regression models were used to determine the relationships.
    Results: In the cross-sectional study, IR showed a positive association with the prevalence of LVH and decreased LVDFpEF after adjusting for confounders. In the longitudinal cohort, IR was also correlated with the new onset of LVH and decreased LVDFpEF, with hazard ratios (HR) of 1.986 (95% CI: 1.307, 3.017) and 1.386 (95% CI: 1.167, 1.647) in the fourth quartile of TyG levels compared to the lowest quartile, respectively, after adjusting for confounders. The subgroup analysis in non-hypertensive or non-diabetic people and the sensitivity analysis in the population with homeostasis model assessment of insulin resistance (HOMA-IR) further verified the above-mentioned results.
    Conclusion: IR was associated with LVH and decreased LVDFpEF. Effective management of IR may prevent or delay the development of adverse LVH and decreased LVDFpEF.
    Keywords:  insulin resistance; left ventricular diastolic function; left ventricular hypertrophy; triglyceride and glucose index
    DOI:  https://doi.org/10.2147/DMSO.S454876
  6. Future Cardiol. 2024 Jun 12. 1-11
    Empagliflozin in the treatment of heart failure.
    Aimen Shafiq, Ishaque Hameed, Jan Biegus, Marat Fudim, Muhammad Shahzeb Khan.
      Heart failure (HF) affects more than 60 million individuals globally. Empagliflozin is currently approved for type 2 diabetes and chronic HF. Clinical trials have demonstrated that empagliflozin reduces the composite end point of hospitalizations for HF and mortality and improves the quality of life irrespective of left ventricular ejection fraction. Empagliflozin is a once-daily medication with minimal drug-drug interactions and does not require titration. Empagliflozin causes mild weight loss and does not significantly reduce blood pressure. Empagliflozin acts as an enabler for other HF drugs by reducing the risk of hyperkalemia. Empagliflozin is also beneficial for chronic kidney disease which exists commonly with HF. This review outlines the pharmacokinetics, pharmacodynamics, safety, and efficacy of empagliflozin in HF across various sub-groups and settings.
    Keywords:  SGLT-2 inhibitor; cardiovascular outcomes; empagliflozin; heart failure; pharmacology
    DOI:  https://doi.org/10.1080/14796678.2024.2360818
  7. Heliyon. 2024 Jun 15. 10(11): e32229
    Liraglutide ameliorates TAC-induced cardiac hypertrophy and heart failure by upregulating expression level of ANP expression.
    Ruisha Li, Keyin Zhang, Zhenjun Xu, Yanrong Yu, Dongjin Wang, Kai Li, Wenxue Liu, Jun Pan.
      Recent studies have underscored the cardioprotective properties of liraglutide. This research explores its impact on cardiac hypertrophy and heart failure following transverse aortic constriction (TAC). We found that liraglutide administration markedly ameliorated cardiac hypertrophy, fibrosis, and function. These benefits correlated with increased ANP expression and reduced activity in the calcineurin A/NFATc3 signaling pathway. Moreover, liraglutide mitigated ER stress and cardiomyocyte apoptosis, and enhanced autophagy. Notably, the positive effects of liraglutide diminished when co-administered with A71915, an ANP inhibitor, suggesting that ANP upregulation is critical to its cardioprotective mechanism.
    Keywords:  ANP; Apoptosis; Cardiac hypertrophy; ER stress; Heart failure; Liraglutide
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e32229
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