bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2023–04–02
ten papers selected by
Kyle McCommis, Saint Louis University
  1. Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation.
  2. Ketones and the Heart: Metabolic Principles and Therapeutic Implications.
  3. Inhibition of Pyruvate Dehydrogenase in the Heart as an Initiating Event in the Development of Diabetic Cardiomyopathy.
  4. Ginsenoside Rb1 promotes the activation of PPARα pathway via inhibiting FADD to ameliorate heart failure.
  5. The Effects of Dapagliflozin in Patients With Heart Failure Complicated With Type 2 Diabetes: A Meta-Analysis of Placebo-Controlled Randomized Trials.
  6. Linagliptin exacerbates heart failure due to energy deficiency via downregulation of glucose utilization and absorption in a mouse model.
  7. Defective Muscle Ketone Body Oxidation Disrupts BCAA Catabolism by Altering Mitochondrial Branched-Chain Aminotransferase.
  8. Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice.
  9. A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure.
  10. Circulating ketone bodies as signals for cardiovascular disease and mortality.
  1. Cardiovasc Diabetol. 2023 Mar 28. 22(1): 73
    Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation.
    Keshav Gopal, Qutuba G Karwi, Seyed Amirhossein Tabatabaei Dakhili, Cory S Wagg, Liyan Zhang, Qiuyu Sun, Christina T Saed, Sai Panidarapu, Riccardo Perfetti, Ravichandran Ramasamy, John R Ussher, Gary D Lopaschuk.
       BACKGROUND: Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodeling. Because disturbances in cardiac energy metabolism can promote cardiac inefficiency, we hypothesized that aldose reductase inhibition may mitigate diabetic cardiomyopathy via normalization of cardiac energy metabolism.
    METHODS: Male C57BL/6J mice (8-week-old) were subjected to experimental type 2 diabetes/diabetic cardiomyopathy (high-fat diet [60% kcal from lard] for 10 weeks with a single intraperitoneal injection of streptozotocin (75 mg/kg) at 4 weeks), following which animals were randomized to treatment with either vehicle or AT-001, a next-generation aldose reductase inhibitor (40 mg/kg/day) for 3 weeks. At study completion, hearts were perfused in the isolated working mode to assess energy metabolism.
    RESULTS: Aldose reductase inhibition by AT-001 treatment improved diastolic function and cardiac efficiency in mice subjected to experimental type 2 diabetes. This attenuation of diabetic cardiomyopathy was associated with decreased myocardial fatty acid oxidation rates (1.15 ± 0.19 vs 0.5 ± 0.1 µmol min-1 g dry wt-1 in the presence of insulin) but no change in glucose oxidation rates compared to the control group. In addition, cardiac fibrosis and hypertrophy were also mitigated via AT-001 treatment in mice with diabetic cardiomyopathy.
    CONCLUSIONS: Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes.
    Keywords:  AT-001; Aldose reductase; Diabetic cardiomyopathy; Diastolic dysfunction; Fatty acid oxidation
    DOI:  https://doi.org/10.1186/s12933-023-01811-w
  2. Circ Res. 2023 Mar 31. 132(7): 882-898
    Ketones and the Heart: Metabolic Principles and Therapeutic Implications.
    Timothy R Matsuura, Patrycja Puchalska, Peter A Crawford, Daniel P Kelly.
      The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.
    Keywords:  3-hydroxybutyric acid; acetoacetate; diet, ketogenic; fatty acid oxidation; heart failure; hypertrophy; ketone bodies
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.321872
  3. Antioxidants (Basel). 2023 Mar 20. pii: 756. [Epub ahead of print]12(3):
    Inhibition of Pyruvate Dehydrogenase in the Heart as an Initiating Event in the Development of Diabetic Cardiomyopathy.
    Abdallah Elnwasany, Heba A Ewida, Pamela A Szweda, Luke I Szweda.
      Obesity affects a growing fraction of the population and is a risk factor for type 2 diabetes and cardiovascular disease. Even in the absence of hypertension and coronary artery disease, type 2 diabetes can result in a heart disease termed diabetic cardiomyopathy. Diminished glucose oxidation, increased reliance on fatty acid oxidation for energy production, and oxidative stress are believed to play causal roles. However, the progression of metabolic changes and mechanisms by which these changes impact the heart have not been established. Cardiac pyruvate dehydrogenase (PDH), the central regulatory site for glucose oxidation, is rapidly inhibited in mice fed high dietary fat, a model of obesity and diabetes. Increased reliance on fatty acid oxidation for energy production, in turn, enhances mitochondrial pro-oxidant production. Inhibition of PDH may therefore initiate metabolic inflexibility and oxidative stress and precipitate diabetic cardiomyopathy. We discuss evidence from the literature that supports a role for PDH inhibition in loss in energy homeostasis and diastolic function in obese and diabetic humans and in rodent models. Finally, seemingly contradictory findings highlight the complexity of the disease and the need to delineate progressive changes in cardiac metabolism, the impact on myocardial structure and function, and the ability to intercede.
    Keywords:  cardiomyopathy; diabetes; metabolic inflexibility; obesity; oxidative stress; pyruvate dehydrogenase
    DOI:  https://doi.org/10.3390/antiox12030756
  4. Eur J Pharmacol. 2023 Mar 29. pii: S0014-2999(23)00187-5. [Epub ahead of print] 175676
    Ginsenoside Rb1 promotes the activation of PPARα pathway via inhibiting FADD to ameliorate heart failure.
    Chuting Li, Xuting Zhang, Jie Li, Liyin Liang, Jingran Zeng, Min Wen, Linjie Pan, Dongxin Lv, Min Liu, Yuanyuan Cheng, Heqing Huang.
       PURPOSE: Ginsenoside Rb1 (GRb1), a dammarane-type triterpene saponin compound mainly distributed in ginseng (Panax ginseng), has been demonstrated to ameliorate cardiovascular diseases. However, it remains unclear whether GRb1 alleviates heart failure (HF) by maintaining cardiac energy metabolism balance. Therefore, this work aimed to investigate the cardiac benefits of GRb1 against cardiac energy deficit and explore its mechanism of action.
    METHODS AND RESULTS: Isoproterenol (ISO) induced HF Sprague-Dawley rats were administrated with GRb1 or fenofibrate for 6 weeks. ISO-induced primary neonatal rat cardiomyocytes (NRCMs) were used as the in vitro model. In vivo, GRb1 significantly improved the structural and metabolic disorder, as demonstrated by the restoration of cardiac function, inhibition of cardiac hypertrophy and fibrosis, and increased adenosine triphosphate (ATP) generation. In vitro, GRb1 effectively protected mitochondrial function and scavenged excessive reactive oxygen species. Moreover, in ISO-induced NRCMs, GRb1 significantly inhibited the abnormal upregulation of Fas-associated death domain (FADD), promoted transcriptional activation of peroxisome proliferator-activated receptor-alpha (PPARα), improved the aberrant expression of cardiac energy metabolism-related enzymes and cardiac fatty acid oxidation, and subsequently increased the synthesis of ATP. Noticeably, GRb1 could inhibit the increased binding between FADD and PPARα, which contributed to the activation of PPARα. Furthermore, GRb1 strengthened the thermal stabilization of FADD and might bind to FADD directly.
    CONCLUSIONS: Collectively, it's part of the in-depth mechanism of GRb1's cardio-protection that GRb1 could directly bind to FADD and counteract its negative role in the transcription of PPARα thus ameliorating cardiac energy derangement and HF.
    Keywords:  Cardiac energy metabolism; FADD; Fatty acid oxidation; Ginsenoside Rb1; Heart failure; PPARα
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175676
  5. Front Clin Diabetes Healthc. 2021 ;2 703937
    The Effects of Dapagliflozin in Patients With Heart Failure Complicated With Type 2 Diabetes: A Meta-Analysis of Placebo-Controlled Randomized Trials.
    Miaobo Zhai, Xin Du, Changmei Liu, Huipu Xu.
       Background: Cardiovascular disease threatens the health and quality of life of individuals, particularly those with type II diabetes. Recently, some studies have reported the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing the rates of hospitalization or urgent visits, resulting in IV therapy for heart failure in patients with type 2 diabetes mellitus (T2DM).
    Methods: We did a comprehensive search in electronic databases from inception through July 2020 for randomized-controlled trials, using the keywords "sodium-glucose cotransporter-2 inhibitor", "dapagliflozin", "heart failure", "cardiovascular outcomes", "major adverse cardiovascular events", "all-cause mortality", and "cardiovascular death". Random-effects summary odds ratios (OR) were constructed using M-L heterogeneity model.
    Results: Five trials with 5,252 patients were ultimately included. The incidence of hospitalization for heart failure (HHF) (n=4, OR=0.74; 95% CI, 0.61 to 0.88; I2 = 0%) and all-cause mortality (ACM, n=4, OR=0.76; 95% CI, 0.66 to 0.94; I2 = 0%); was reduced by dapagliflozin, respectively, in all heart failure patients, without obvious heterogeneity. The incidence of cardiovascular death in dapagliflozin was lower than that in placebo without statistically significant (CVD, n=5, OR=0.84; 95% CI, 0.69 to 1.03; I2 = 0%). In HFrEF subgroup, dapagliflozin was associated with a reduced incidence of hospitalization for heart failure (n=4, OR=0.74; 95% CI, 0.60 to 0.91; I2 = 0%), cardiovascular death (n=4, OR=0.72; 95% CI, 0.58 to 0.91; I2 = 8%), and all-cause mortality (n=3, OR=0.70; 95% CI, 0.50 to 0.99; I2 = 43%) without significant heterogeneity. In contrast, in the HFpEF subgroup, there was no difference in the incidence of cardiovascular death (n=2, OR=1.45; 95% CI, 0.95 to 2.22; I2 = 0%) and all-cause mortality (n=2, OR=1.04; 95% CI, 0.76 to 1.43; I2 = 0%) between dapagliflozin and placebo.
    Conclusion: In our study, dapagliflozin performed a statistical reduction in the rate of heart failure hospitalization, cardiovascular death, and all-cause mortality in patients with HFrEF and diabetes. However, in the HFpEF subgroup, dapagliflozin did not show a significant cardiovascular protective effect.
    Keywords:  dapagliflozin; heart failure; meta-analysis; randomized controlled trial; type 2 diabetes
    DOI:  https://doi.org/10.3389/fcdhc.2021.703937
  6. Eur J Pharmacol. 2023 Mar 23. pii: S0014-2999(23)00184-X. [Epub ahead of print] 175673
    Linagliptin exacerbates heart failure due to energy deficiency via downregulation of glucose utilization and absorption in a mouse model.
    Aya Shiraki, Jun-Ichi Oyama, Takahiko Shimizu, Koichi Node.
      Use of dipeptidyl peptidase-4 (DPP4) inhibitor in some clinical trials might have caused heart failure (HF), leading to increased hospitalizations. The aim of the present study was to determine whether linagliptin has any effect on chronic dilated HF, and its underlying mechanisms. Physiologic and pathologic studies were conducted on heart/muscle-specific manganese superoxide dismutase-deficient mice, which exhibited dilated cardiomyopathy, and were randomized to receive a low dose (1 mg/kg, HF-L group) or high dose (10 mg/kg, HF-H group) mixed with food, or normal food (HF group), for 8 weeks. Linagliptin increased mortality and heart/body weight ratio in mice with HF. Cardiac contractility and fibrosis worsened, whereas hepatic glycogen content and individual carbohydrate consumption decreased significantly in the HF-H group, when compared with the HF control group. Therefore, we performed a complementary experiment by supplementing glucose to the mice treated with high-dose linagliptin (HF-HG group). Adequate glucose supplementation reduced heart/body weight ratio and cardiac fibrosis, and improved cardiac contractility, without changing mortality. Following oral administration of 13C glucose, the respiratory 13C decreased in the HF-H and HF-HG groups, when compared with that in the HF group; the fecal 13C increased, suggesting that linagliptin inhibited glucose absorbance in the intestine. In addition, the expression of GLUT2, a glucose transporter was downregulated in the small intestine. Linagliptin treatment exacerbated HF, which increased mortality, cardiac function, and fibrosis. DPP4 inhibitors might boost cardiac cachexia and exacerbate HF, at least in part, through the modification of glucose utilization and absorption.
    Keywords:  DPP4 inhibitor; GLP-1; Glucose; Heart failure; Malabsorption; Metabolism
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175673
  7. Am J Physiol Endocrinol Metab. 2023 Mar 29.
    Defective Muscle Ketone Body Oxidation Disrupts BCAA Catabolism by Altering Mitochondrial Branched-Chain Aminotransferase.
    Hamza Mechchate, Abdualrahman Mohammed Abdualkader, James Bradshaw Bernacchi, Keshav Gopal, S Amirhossein Tabatabaei Dakhili, Kunyan Yang, Amanda A Greenwell, Xingxing Kong, Peter A Crawford, Rami Al Batran.
      Ketone bodies are an endogenous fuel source generated primarily by the liver to provide alternative energy for extrahepatic tissues during prolonged fasting and exercise. Skeletal muscle is an important site of ketone body oxidation which occurs through a series of reactions requiring the enzyme succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1). We have previously shown that deleting SCOT in the skeletal muscle protects against obesity-induced insulin resistance by increasing pyruvate dehydrogenase (PDH) activity, the rate-limiting enzyme of glucose oxidation. However, it remains unclear whether inhibiting muscle ketone body oxidation causes hypoglycemia and affects fuel metabolism in the absence of obesity. Here, we show that lean mice lacking skeletal muscle SCOT (SCOTSkM-/-) exhibited no overt phenotypic differences in glucose and fat metabolism from their human α-skeletal actin-Cre (HSACre) littermates. Of interest, we found that plasma and muscle branched-chain amino acid (BCAA) levels are elevated in SCOTSkM-/- lean mice compared to their HSACre littermates. Interestingly, this alteration in BCAA catabolism was only seen in SCOTSkM-/- mice under low-fat feeding and associated with decreased expression of mitochondrial branched-chain aminotransferases (BCATm/Bcat2), the first enzyme in BCAA catabolic pathway. Loss- and gain-of-function studies in C2C12 myotubes demonstrated that suppressing SCOT markedly diminished BCATm expression, whereas overexpressing SCOT resulted in an opposite effect without influencing BCAA oxidation enzymes. Further, SCOT overexpression in C2C12 myotubes significantly increased luciferase activity driven by a Bcat2 promoter construct. Together, our findings indicate that SCOT regulates the expression of the Bcat2 gene, which, through the abundance of its product BCATm, may influence circulating BCAA concentrations.
    Keywords:  BCAAs; BCATm; Ketone body; SCOT; Skeletal Muscle
    DOI:  https://doi.org/10.1152/ajpendo.00206.2022
  8. Acta Pharmacol Sin. 2023 Mar 29.
    Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice.
    Jia-Yu Yu, Nancy Cao, Christoph D Rau, Ro-Po Lee, Jieping Yang, Rachel J Roth Flach, Lauren Petersen, Cansheng Zhu, Yea-Lyn Pak, Russell A Miller, Yunxia Liu, Yibin Wang, Zhaoping Li, Haipeng Sun, Chen Gao.
      Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy.
    Keywords:  branched-chain amino acid; heart failure; metabolism
    DOI:  https://doi.org/10.1038/s41401-023-01076-9
  9. Front Cardiovasc Med. 2023 ;10 1130635
    A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure.
    Zhenya Wang, Wei Shi, Taibo Wu, Tian Peng, Xiaoming Wang, Shuaiyang Liu, Zifeng Yang, Jia Wang, Peng-Long Li, Ruifeng Tian, Ying Hong, Hailong Yang, Lan Bai, Yufeng Hu, Xu Cheng, Hongliang Li, Xiao-Jing Zhang, Zhi-Gang She.
       Background: Pathological cardiac hypertrophy is commonly resulted from sustained pressure overload and/or metabolic disorder and eventually leads to heart failure, lacking specific drugs in clinic. Here, we aimed to identify promising anti-hypertrophic drug(s) for heart failure and related metabolic disorders by using a luciferase reporter-based high-throughput screening.
    Methods: A screen of the FDA-approved compounds based on luciferase reporter was performed, with identified luteolin as a promising anti-hypertrophic drug. We systematically examined the therapeutic efficacy of luteolin on cardiac hypertrophy and heart failure in vitro and in vivo models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin.
    Results: Among 2,570 compounds in the library, luteolin emerged as the most robust candidate against cardiomyocyte hypertrophy. Luteolin dose-dependently blocked phenylephrine-induced cardiomyocyte hypertrophy and showed extensive cardioprotective roles in cardiomyocytes as evidenced by transcriptomics. More importantly, gastric administration of luteolin effectively ameliorated pathological cardiac hypertrophy, fibrosis, metabolic disorder, and heart failure in mice. Cross analysis of large-scale transcriptomics and drug-target interacting investigations indicated that peroxisome proliferator activated receptor γ (PPARγ) was the direct target of luteolin in the setting of pathological cardiac hypertrophy and metabolic disorders. Luteolin can directly interact with PPARγ to inhibit its ubiquitination and subsequent proteasomal degradation. Furthermore, PPARγ inhibitor and PPARγ knockdown both prevented the protective effect of luteolin against phenylephrine-induced cardiomyocyte hypertrophy in vitro.
    Conclusion: Our data clearly supported that luteolin is a promising therapeutic compound for pathological cardiac hypertrophy and heart failure by directly targeting ubiquitin-proteasomal degradation of PPARγ and the related metabolic homeostasis.
    Keywords:  cardiac hypertrophy; fatty acid metabolism; glucose metabolism; heart failure; luteolin; peroxisome proliferator activated receptor γ
    DOI:  https://doi.org/10.3389/fcvm.2023.1130635
  10. Eur Heart J. 2023 Mar 30. pii: ehad176. [Epub ahead of print]
    Circulating ketone bodies as signals for cardiovascular disease and mortality.
    Suzanne N Voorrips, B Daan Westenbrink.
      
    DOI:  https://doi.org/10.1093/eurheartj/ehad176
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