bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2022‒05‒08
seven papers selected by
Kyle McCommis
Saint Louis University
  1. Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure with Reduced Ejection Fraction: Current Evidence and Future Perspectives.
  2. The Effect of Empagliflozin on Contractile Reserve in Heart Failure: Prespecified Sub-Study of a Randomized, Double-Blind, and Placebo-Controlled Trial.
  3. Ketone body and FGF21 coordinately regulate fasting-induced oxidative stress response in the heart.
  4. Ginsenoside Rg3 ameliorates myocardial glucose metabolism and insulin resistance via activating the AMPK signaling pathway.
  5. Combined metabolomic and transcriptomic profiling approaches reveal the cardiac response to high-fat diet.
  6. Triglyceride-glucose index in the development of heart failure and left ventricular dysfunction: analysis of the ARIC study.
  7. The Polyunsaturated Fatty Acids, EPA and DHA, Ameliorate Myocardial Infarction-induced Heart Failure by Inhibiting p300-HAT Activity in Rats.
  1. Basic Clin Pharmacol Toxicol. 2022 May 05.
    Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure with Reduced Ejection Fraction: Current Evidence and Future Perspectives.
    Jesper Jensen, Massar Omar, Caroline Kistorp, Finn Gustafsson, Lars Køber, Jacob Eifer Møller, Morten Schou.
      BACKGROUND: The sodium-glucose cotransporter-2 (SGLT2) inhibitors were developed as glucose-lowering drugs to treat type 2 diabetes (T2D). However, significant reductions in clinical outcomes have now been demonstrated in patients with heart failure with reduced ejection fraction (HFrEF), irrespective of the presence of T2D. Multiple hypotheses have been proposed for the underlying mechanisms and the data to support these proposals are emerging.OBJECTIVES: To review the clinical outcome data with SGLT2 inhibitors in HFrEF and the data to support the mechanisms for these clinical effects.
    METHODS: Literature review, supported by a PubMed search for relevant articles up to April 19, 2022.
    FINDINGS: Current data support increased diuresis and reverse cardiac remodelling as important mechanisms for the reductions in heart failure hospitalisations and mortality observed with SGLT2 inhibitors (empagliflozin or dapagliflozin) in patients with HFrEF. Alteration in intrarenal haemodynamic is likely contributing to the observed renoprotective effect of SGLT2 inhibitors.
    CONCLUSIONS: Solid clinical data support the current recommendations to use empagliflozin or dapagliflozin in HFrEF. The underlying mechanisms likely include changes in cardiac and intrarenal haemodynamic. Yet, these mechanisms do not seem to solely explain the observed magnitude of clinical effect with SGLT2 inhibitors in HFrEF and other mechanisms may contribute.
    Keywords:  Clinical; Heart Failure; Mechanisms; SGLT2 Inhibitors; Treatment
    DOI:  https://doi.org/10.1111/bcpt.13739
  2. Am Heart J. 2022 May 02. pii: S0002-8703(22)00083-7. [Epub ahead of print]
    The Effect of Empagliflozin on Contractile Reserve in Heart Failure: Prespecified Sub-Study of a Randomized, Double-Blind, and Placebo-Controlled Trial.
    Jesper Jensen, Massar Omar, Mulham Ali, Peter H Frederiksen, Caroline Kistorp, Christian Tuxen, Camilla F Andersen, Julie H Larsen, Mads Kristian Ersbøll, Lars Køber, Finn Gustafsson, Jens Faber, Julie Lyng Forman, Jacob Eifer Møller, Morten Schou.
      BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve cardiac structure but most studies suggest no change in left ventricular (LV) systolic function at rest. Whether SGLT2 inhibitors improve LV contractile reserve is unknown. We investigated the effect of empagliflozin on LV contractile reserve in patients with heart failure (HF) and reduced ejection fraction (HFrEF).METHODS: Prespecified sub-study of the Empire HF trial, a double-blind, placebo-controlled, and randomized trial. Patients with LV ejection fraction (LVEF) ≤40% on guideline-directed HF therapy were randomized (1:1) to empagliflozin 10 mg or placebo for 12 weeks. The treatment effect on contractile reserve was assessed by low dose dobutamine stress echocardiography.
    RESULTS: In total, 120 patients were included. The mean age was 68 (SD 10) years, 83% were male, and the mean LVEF was 38 (SD 10) %. Respectively 60 (100%) and 59 (98%) patients in the empagliflozin and placebo groups completed stress echocardiography. No statistically significant effect of empagliflozin was observed for the contractile reserve assessed by LV-GLS [adjusted mean absolute change, empagliflozin versus placebo, 0.7% (95% CI -0.5 to 2.0, P=0.25)] or LVEF [adjusted mean absolute change, empagliflozin versus placebo, 2.2% (95% CI -1.4 to 5.8, P=0.22)] from baseline to 12 weeks. LV-GLS contractile reserve was associated with accelerometer-measured daily activity level [coefficient -24 accelerometer counts (95% CI -46 to -1.8, P=0.03)].
    CONCLUSIONS: Empagliflozin for 12 weeks added to guideline-directed HF therapy did not improve LV contractile reserve in patients with HFrEF.
    REGISTRATION: NCT03198585. https://www.
    CLINICALTRIALS: gov/ct2/show/NCT03198585?term=Empire±HF&draw=2&rank=1.
    Keywords:  Clinical Studies; Contractile Function; Echocardiography; Heart Failure; Treatment
    DOI:  https://doi.org/10.1016/j.ahj.2022.04.008
  3. Sci Rep. 2022 May 05. 12(1): 7338
    Ketone body and FGF21 coordinately regulate fasting-induced oxidative stress response in the heart.
    Ryo Kawakami, Hiroaki Sunaga, Tatsuya Iso, Ryosuke Kaneko, Norimichi Koitabashi, Masaru Obokata, Tomonari Harada, Hiroki Matsui, Tomoyuki Yokoyama, Masahiko Kurabayashi.
      Ketone body β-hydroxybutyrate (βOHB) and fibroblast growth factor-21 (FGF21) have been proposed to mediate systemic metabolic response to fasting. However, it remains elusive about the signaling elicited by ketone and FGF21 in the heart. Stimulation of neonatal rat cardiomyocytes with βOHB and FGF21 induced peroxisome proliferator-activated receptor α (PPARα) and PGC1α expression along with the phosphorylation of LKB1 and AMPK. βOHB and FGF21 induced transcription of peroxisome proliferator-activated receptor response element (PPRE)-containing genes through an activation of PPARα. Additionally, βOHB and FGF21 induced the expression of Nrf2, a master regulator for oxidative stress response, and catalase and Ucp2 genes. We evaluated the oxidative stress response gene expression after 24 h fast in global Fgf21-null (Fgf21-/-) mice, cardiomyocyte-specific FGF21-null (cmFgf21-/-) mice, wild-type (WT), and Fgf21fl/fl littermates. Fgf21-/- mice but not cmFgf21-/- mice had unexpectedly higher serum βOHB levels, and higher expression levels of PPARα and oxidative stress response genes than WT mice or Fgf21fl/fl littermates. Notably, expression levels of oxidative stress response genes were significantly correlated with serum βOHB and PGC1α levels in both WT and Fgf21-/- mice. These findings suggest that fasting-induced βOHB and circulating FGF21 coordinately regulate oxidative stress response gene expression in the heart.
    DOI:  https://doi.org/10.1038/s41598-022-10993-4
  4. J Ginseng Res. 2022 Mar;46(2): 235-247
    Ginsenoside Rg3 ameliorates myocardial glucose metabolism and insulin resistance via activating the AMPK signaling pathway.
    Jingyu Ni, Zhihao Liu, Miaomiao Jiang, Lan Li, Jie Deng, Xiaodan Wang, Jing Su, Yan Zhu, Feng He, Jingyuan Mao, Xiumei Gao, Guanwei Fan.
      Background: Ginsenoside Rg3 is one of the main active ingredients in ginseng. Here, we aimed to confirm its protective effect on the heart function in transverse aortic coarctation (TAC)-induced heart failure mice and explore the potential molecular mechanisms involved.Methods: The effects of ginsenoside Rg3 on heart and mitochondrial function were investigated by treating TAC-induced heart failure in mice. The mechanism of ginsenoside Rg3 for improving heart and mitochondrial function in mice with heart failure was predicted through integrative analysis of the proteome and plasma metabolome. Glucose uptake and myocardial insulin sensitivity were evaluated using micro-positron emission tomography. The effect of ginsenoside Rg3 on myocardial insulin sensitivity was clarified by combining in vivo animal experiments and in vitro cell experiments.
    Results: Treatment of TAC-induced mouse models with ginsenoside Rg3 significantly improved heart function and protected mitochondrial structure and function. Fusion of metabolomics, proteomics, and targeted metabolomics data showed that Rg3 regulated the glycolysis process, and Rg3 not only regulated glucose uptake but also improve myocardial insulin resistance. The molecular mechanism of ginsenoside Rg3 regulation of glucose metabolism was determined by exploring the interaction pathways of AMPK, insulin resistance, and glucose metabolism. The effect of ginsenoside Rg3 on the promotion of glucose uptake in IR-H9c2 cells by AMPK activation was dependent on the insulin signaling pathway.
    Conclusions: Ginsenoside Rg3 modulates glucose metabolism and significantly ameliorates insulin resistance through activation of the AMPK pathway.
    Keywords:  AMPK; Ginsenoside Rg3; Glucose metabolism; Heart failure; Insulin resistance
    DOI:  https://doi.org/10.1016/j.jgr.2021.06.001
  5. iScience. 2022 May 20. 25(5): 104184
    Combined metabolomic and transcriptomic profiling approaches reveal the cardiac response to high-fat diet.
    Leroy C Joseph, Jianting Shi, Quynh N Nguyen, Victoria Pensiero, Chris Goulbourne, Robert C Bauer, Hanrui Zhang, John P Morrow.
      The response of vital organs to different types of nutrition or diet is a fundamental question in physiology. We examined the cardiac response to 4 weeks of high-fat diet in mice, measuring cardiac metabolites and mRNA. Metabolomics showed dramatic differences after a high-fat diet, including increases in several acyl-carnitine species. The RNA-seq data showed changes consistent with adaptations to use more fatty acid as substrate and an increase in the antioxidant protein catalase. Changes in mRNA were correlated with changes in protein level for several highly responsive genes. We also found significant sex differences in both metabolomics and RNA-seq datasets, both at baseline and after high fat diet. This work reveals the response of a vital organ to dietary intervention at both metabolomic and transcriptomic levels, which is a fundamental question in physiology. This work also reveals significant sex differences in cardiac metabolites and gene expression.
    Keywords:  Human metabolism; Metabolomics; Pathophysiology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.104184
  6. Eur J Prev Cardiol. 2022 May 04. pii: zwac058. [Epub ahead of print]
    Triglyceride-glucose index in the development of heart failure and left ventricular dysfunction: analysis of the ARIC study.
    Rihua Huang, Yifen Lin, Xiaomin Ye, Xiangbin Zhong, Peihan Xie, Miaohong Li, Xiaodong Zhuang, Xinxue Liao.
      AIMS: We aimed to investigate whether the triglyceride-glucose (TyG) index, an easy-calculated and reliable surrogate of insulin resistance, was associated with the development of heart failure (HF) and left ventricular (LV) dysfunction.METHODS AND RESULTS: A total of 12 374 participants (mean age: 54.1 ± 5.7 years, male: 44.7%) free of history of HF and coronary heart disease at baseline from the Atherosclerosis Risk in Communities study were included. The TyG index was calculated as ln[fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The long-term TyG index was calculated as the updated cumulative average TyG index using all available TyG index from baseline to the events of HF or the end of follow-up. We evaluated the associations of both the baseline and the long-term TyG index with incident HF using Cox regression analysis. We also analysed the effect of the TyG index on LV structure and function among 4889 participants with echocardiographic data using multivariable linear regression analysis. There were 1958 incident HF cases over a median follow-up of 22.5 years. After adjusting for potential confounders, 1-SD (0.60) increase in the baseline TyG index was associated with a 15% higher risk of HF development [hazard ratio (HR): 1.15, 95% confidence interval (CI): 1.10-1.21]. Compared with participants in the lowest quartile of the baseline TyG index, those in the highest quartile had a greater risk of incident HF [HR (95% CI): 1.25 (1.08-1.45)]. In terms of LV structure and function, a greater baseline TyG index was associated with adverse LV remodelling and LV dysfunction. Similar results were found for the long-term TyG index.
    CONCLUSION: In a community-based cohort, we found that a greater TyG index was significantly associated with a higher risk of incident HF and impaired LV structure and function.
    Keywords:  Heart failure; Insulin resistance; Left ventricle; Triglyceride–glucose index
    DOI:  https://doi.org/10.1093/eurjpc/zwac058
  7. J Nutr Biochem. 2022 Apr 30. pii: S0955-2863(22)00102-4. [Epub ahead of print] 109031
    The Polyunsaturated Fatty Acids, EPA and DHA, Ameliorate Myocardial Infarction-induced Heart Failure by Inhibiting p300-HAT Activity in Rats.
    Yoichi Sunagawa, Ayumi Katayama, Masafumi Funamoto, Kana Shimizu, Satoshi Shimizu, Sari Nurmila, Yasufumi Katanasaka, Yusuke Miyazaki, Ryota Hosomi, Koji Hasegawa, Tatsuya Morimoto.
      INTRODUCTION: While the cardioprotective functions of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and omega-3 unsaturated fatty acids have been previously demonstrated, little is known about their effects on cardiomyocyte hypertrophy. In this study, we compared the effects of EPA and DHA on hypertrophic responses in cardiomyocytes and development of heart failure in rats with myocardial infarction (MI).METHODS AND RESULTS: Both EPA and DHA significantly suppressed phenylephrine- and p300-induced cardiomyocyte hypertrophy, transcription of hypertrophy response genes, and acetylation of histone H3K9 in cardiomyocytes. EPA and DHA directly inhibited p300-histone acetyltransferase activity (IC50: 37.8 and 30.6 μM, respectively). Further, EPA and DHA induced allosteric inhibition of histones and competitive inhibition of acetyl-CoA, and significantly prevented p300-induced hypertrophic responses. Rats with moderate MI (left ventricular fractional shortening [FS] < 40%) were randomly assigned to three groups, namely, vehicle (saline), EPA (1 g/kg), and DHA (1 g/kg). One week after the operation, rats were orally administrated with test agents for 6 weeks. Echocardiographic analysis demonstrated that both EPA and DHA treatments preserved FS and prevented MI-induced left ventricular remodeling. Furthermore, EPA and DHA significantly suppressed the MI-induced increase in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers, fibrosis, and acetylation of histone H3K9. The effects on hypertrophic responses and the development of heart failure were not different between EPA and DHA groups.
    CONCLUSION: Both EPA and DHA suppressed hypertrophic responses and the development of heart failure to the same extent through the inhibition of p300-HAT activity.
    Keywords:  acetyltransferase; cardiomyocyte hypertrophy; docosahexaenoic acid; eicosapentaenoic acid; heart failure; omega-3 polyunsaturated fatty acid; p300
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109031
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