bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2021–09–05
ten papers selected by
Kyle McCommis, Saint Louis University
  1. Molecular Signature of HFpEF: Systems Biology in a Cardiac-Centric Large Animal Model.
  2. Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart.
  3. FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway.
  4. FUNCTIONAL RESILIENCE OF C57BL/6J MOUSE HEART TO DIETARY FAT OVERLOAD.
  5. Ketone bodies for the failing heart: fuels that can fix the engine?
  6. Mito-targeted antioxidant prevents cardiovascular remodelling in spontaneously hypertensive rat by modulation of energy metabolism.
  7. The Role of SGLT2 Inhibitors in Heart Failure: A Systematic Review and Meta-Analysis.
  8. Sodium-glucose co-transporter-2 inhibitors eligibility in patients with heart failure with reduced ejection fraction.
  9. Effect of Empagliflozin on Worsening Heart Failure Events in Patients with Heart Failure and a Preserved Ejection Fraction: The EMPEROR-Preserved Trial.
  10. Effect of canagliflozin on N-terminal pro-brain natriuretic peptide in patients with type 2 diabetes and chronic heart failure according to baseline use of glucose-lowering agents.
  1. JACC Basic Transl Sci. 2021 Aug;6(8): 650-672
    Molecular Signature of HFpEF: Systems Biology in a Cardiac-Centric Large Animal Model.
    Andrew A Gibb, Emma K Murray, Deborah M Eaton, Anh T Huynh, Dhanendra Tomar, Joanne F Garbincius, Devin W Kolmetzky, Remus M Berretta, Markus Wallner, Steven R Houser, John W Elrod.
      In this study the authors used systems biology to define progressive changes in metabolism and transcription in a large animal model of heart failure with preserved ejection fraction (HFpEF). Transcriptomic analysis of cardiac tissue, 1-month post-banding, revealed loss of electron transport chain components, and this was supported by changes in metabolism and mitochondrial function, altogether signifying alterations in oxidative metabolism. Established HFpEF, 4 months post-banding, resulted in changes in intermediary metabolism with normalized mitochondrial function. Mitochondrial dysfunction and energetic deficiencies were noted in skeletal muscle at early and late phases of disease, suggesting cardiac-derived signaling contributes to peripheral tissue maladaptation in HFpEF. Collectively, these results provide insights into the cellular biology underlying HFpEF progression.
    Keywords:  BCAA, branched chain amino acids; DAG, diacylglycerol; ECM, extracellular matrix; EF, ejection fraction; ESI, electrospray ionization; ETC, electron transport chain; FC, fold change; FDR, false discovery rate; GO, gene ontology; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LA, left atrial; LAV, left atrial volume; LV, left ventricle/ventricular; MS/MS, tandem mass spectrometry; RCR, respiratory control ratio; RI, retention index; UPLC, ultraperformance liquid chromatography; heart failure; m/z, mass to charge ratio; metabolomics; mitochondria; preserved ejection fraction; systems biology; transcriptomics
    DOI:  https://doi.org/10.1016/j.jacbts.2021.07.004
  2. Metabolism. 2021 Aug 31. pii: S0026-0495(21)00171-2. [Epub ahead of print] 154871
    Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart.
    Golam M Uddin, Qutuba G Karwi, Simran Pherwani, Keshav Gopal, Cory S Wagg, Dipsikha Biswas, Mariam Atnasious, Yikuan Wu, Guoqing Wu, Liyan Zhang, Kim L Ho, Thomas Pulinilkunnil, John R Ussher, Gary D Lopaschuk.
       BACKGROUNDS: Branched chain amino acid (BCAA) oxidation is impaired in cardiac insulin resistance, leading to the accumulation of BCAAs and the first products of BCAA oxidation, the branched chain ketoacids. However, it is not clear whether it is the BCAAs, BCKAs or both that are mediating cardiac insulin resistance. To determine this, we produced mice with a cardiac-specific deletion of BCAA aminotransferase (BCATm-/-), the first enzyme in the BCAA oxidation pathway that is responsible for converting BCAAs to BCKAs.
    METHODS: Eight-week-old BCATm cardiac specific knockout (BCATm-/-) male mice and their α-MHC (myosin heavy chain) - Cre expressing wild type littermates (WT-Cre+/+) received tamoxifen (50 mg/kg i.p. 6 times over 8 days). At 16-weeks of age, cardiac energy metabolism was assessed in isolated working hearts.
    RESULTS: BCATm-/- mice have decreased cardiac BCAA oxidation rates, increased cardiac BCAAs and a reduction in cardiac BCKAs. Hearts from BCATm-/- mice showed an increase in insulin stimulation of glucose oxidation and an increase in p-AKT. To determine the impact of reversing these events, we perfused isolated working mice hearts with high levels of BCKAs, which completely abolished insulin-stimulated glucose oxidation rates, an effect associated with decreased p-AKT and inactivation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme in glucose oxidation.
    CONCLUSION: This implicates the BCKAs, and not BCAAs, as the actual mediators of cardiac insulin resistance and suggests that lowering cardiac BCKAs can be used as a therapeutic strategy to improve insulin sensitivity in the heart.
    Keywords:  Branched chain amino acids; Branched chain keto acids; Cardiac insulin signaling; Glucose oxidation; Metabolism; Mitochondrial branched chain aminotransferase
    DOI:  https://doi.org/10.1016/j.metabol.2021.154871
  3. Front Cardiovasc Med. 2021 ;8 722908
    FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway.
    Lingfang Zhuang, Ye Mao, Zizhu Liu, Chenni Li, Qi Jin, Lin Lu, Rong Tao, Xiaoxiang Yan, Kang Chen.
      Background: Cardiac hypertrophy was accompanied by various cardiovascular diseases (CVDs), and due to the high global incidence and mortality of CVDs, it has become increasingly critical to characterize the pathogenesis of cardiac hypertrophy. We aimed to determine the metabolic roles of fatty acid binding protein 3 (FABP3) on transverse aortic constriction (TAC)-induced cardiac hypertrophy. Methods and Results: Transverse aortic constriction or Ang II treatment markedly upregulated Fabp3 expression. Notably, Fabp3 ablation aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction. Multi-omics analysis revealed that Fabp3-deficient hearts exhibited disrupted metabolic signatures characterized by increased glycolysis, toxic lipid accumulation, and compromised fatty acid oxidation and ATP production under hypertrophic stimuli. Mechanistically, FABP3 mediated metabolic reprogramming by directly interacting with PPARα, which prevented its degradation and synergistically modulated its transcriptional activity on Mlycd and Gck. Finally, treatment with the PPARα agonist, fenofibrate, rescued the pro-hypertrophic effects of Fabp3 deficiency. Conclusions: Collectively, these findings reveal the indispensable roles of the FABP3-PPARα axis on metabolic homeostasis and the development of hypertrophy, which sheds new light on the treatment of hypertrophy.
    Keywords:  FAO; HFABP; PPARα; cardiac hypertrophy; glycolysis; metabolism
    DOI:  https://doi.org/10.3389/fcvm.2021.722908
  4. Am J Physiol Heart Circ Physiol. 2021 Sep 03.
    FUNCTIONAL RESILIENCE OF C57BL/6J MOUSE HEART TO DIETARY FAT OVERLOAD.
    Satya Murthy Tadinada, Eric T Weatherford, Greg V Collins, Gourav Bhardwaj, Jesse Cochran, William Kutschke, Kathy Zimmerman, Alyssa Bosko, Brian T O'Neill, Robert M Weiss, E Dale Abel.
      Molecular mechanisms underlying cardiac dysfunction and subsequent heart failure in diabetic cardiomyopathy are incompletely understood. Initially we intended to test the role of GRK2, a potential mediator of cardiac dysfunction in diabetic cardiomyopathy, but found that control animals on HFD did not develop cardiomyopathy. Cardiac function was preserved in both wildtype and GRK2 knockout animals fed high fat diet as indicated by preserved left ventricular ejection fraction (LVEF) although heart mass was increased. The absence of cardiac dysfunction led us to rigorously evaluate the utility of diet-induced obesity to model diabetic cardiomyopathy in mice. Using pure C57BL/6J animals and various diets formulated with different sources of fat- lard (32% saturated fat, 68% unsaturated fat) or hydrogenated coconut oil (95% saturated fat), we consistently observed left ventricular hypertrophy, preserved LVEF and preserved contractility measured by invasive hemodynamics in animals fed high fat diet. Gene expression patterns that characterize pathological hypertrophy were not induced but a modest induction of various collagen isoforms and matrix metalloproteinases were observed in heart with high fat diet feeding. PPARa-target genes that enhance lipid utilization such as Pdk4, CD36, AcadL and Cpt1b were induced, but mitochondrial energetics were not impaired. These results suggest while long-term fat feeding in mice induces cardiac hypertrophy and increases cardiac fatty acid metabolism, it may not be sufficient to activate pathological hypertrophic mechanisms that impair cardiac function or induce cardiac fibrosis. Thus, additional factors that are currently not understood may contribute to the cardiac abnormalities previously reported by many groups.
    Keywords:  Cardiac function; Diabetic cardiomyopathy; High fat diet; Mitochondria; Type 2 Diabetes
    DOI:  https://doi.org/10.1152/ajpheart.00419.2021
  5. Trends Endocrinol Metab. 2021 Aug 26. pii: S1043-2760(21)00172-7. [Epub ahead of print]
    Ketone bodies for the failing heart: fuels that can fix the engine?
    Salva R Yurista, Christopher T Nguyen, Anthony Rosenzweig, Rudolf A de Boer, B Daan Westenbrink.
      Accumulating evidence suggests that the failing heart reverts energy metabolism toward increased utilization of ketone bodies. Despite many discrepancies in the literature, evidence from both bench and clinical research demonstrates beneficial effects of ketone bodies in heart failure. Ketone bodies are readily oxidized by cardiomyocytes and can provide ancillary fuel for the energy-starved failing heart. In addition, ketone bodies may help to restore cardiac function by mitigating inflammation, oxidative stress, and cardiac remodeling. In this review, we hypothesize that a therapeutic approach intended to restore cardiac metabolism through ketone bodies could both refuel and 'repair' the failing heart.
    Keywords:  cardiac metabolism; heart failure; ketone bodies; ketosis
    DOI:  https://doi.org/10.1016/j.tem.2021.07.006
  6. Clin Exp Pharmacol Physiol. 2021 Aug 30.
    Mito-targeted antioxidant prevents cardiovascular remodelling in spontaneously hypertensive rat by modulation of energy metabolism.
    Potnuri Ajay Godwin, Sreeja Purushothaman, Sherin Saheera, Renuka R Nair.
      Hypertension induced left ventricular hypertrophy (LVH) augments the risk of cardiovascular anomalies. Mitochondrial alterations result in oxidative stress,accompanied by decrease in fatty acid oxidation, leading to the activation of the hypertrophic program. Targeted antioxidants are expected to reduce mitochondrial reactive oxygen species more effectively than general antioxidants. This study was designed to assess whether mito-targeted antioxidant, Mito-Tempol (Mito-TEMP) is more effective than general oxidant, Tempol (TEMP)in reduction of hypertension and hypertrophy and prevention of shift in cardiac energy metabolism. Spontaneously Hypertensive Rat were administered either TEMP (20mg/kg/day) or Mito-TEMP (2mg/kg/day) intraperitoneally for 30 days. Post treatment, animals were subjected to 2D-echocardiography. Myocardial lysates were subjected to RPLC - LTQ-Orbitrap-MS analysis. Mid-ventricular sections were probed for markers of energy metabolism and fibrosis. The beneficial effect on cardiovascular structure and function was significantly higher for Mito-TEMP. Increase in mitochondrial antioxidants and stimulation of fatty acid metabolism; with significant improvement in cardiovascular function was apparent in SHR treated with Mito-TEMP. The study indicates that Mito-TEMP is superior to its non- targeted isoform in preventing hypertension induced LVH, and the beneficial effects on heart are possibly mediated by reversal of metabolic remodelling.
    Keywords:  Cardiac Hypertrophy; Cardiac Metabolism; LC-MS; Mitochondria Targeted Antioxidant; Proteomic Analysis; Spontaneously Hypertensive Rat
    DOI:  https://doi.org/10.1111/1440-1681.13585
  7. Cardiol Res Pract. 2021 ;2021 9927533
    The Role of SGLT2 Inhibitors in Heart Failure: A Systematic Review and Meta-Analysis.
    Vasiliki Tsampasian, Ranu Baral, Rahul Chattopadhyay, Maciej Debski, Shruti S Joshi, Johannes Reinhold, Marc R Dweck, Pankaj Garg, Vassilios S Vassiliou.
       Aims: Recent randomised controlled trials (RCTs) have shown a significant prognostic benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the cardiovascular (CV) profile of patients with diabetes. This systematic review and meta-analysis aim to provide a concise evaluation of all the available evidence for the use of these agents in patients with heart failure (HF) regardless of their baseline diabetes status.
    Methods and Results: PubMed, Web of Science, and Cochrane library databases were systematically searched from inception until November 20th 2020. Eight studies consisting of 13,275 patients were included in the meta-analysis. For the total population, SGLT2 inhibitors reduced the risk of all-cause mortality (HR: 0.83; 95% CI: 0.75-0.91; I 2 0%), hospitalisation for HF (HR: 0.68; 95% CI: 0.61-0.75; I 2: 0%), CV death (HR: 0.82; 95% CI: 0.74-0.92; I 2: 0%), and hospitalisation for HF or CV death (HR: 0.72; 95% CI: 0.66-0.78; I 2: 0%). Subgroup analyses of the total population according to the diabetes status showed that SGLT2 inhibitors significantly reduced the risk of hospitalisation for HF (HR: 0.68; 95% CI: 0.61, 0.75; I 2: 0%), as well as the risk of hospitalisation for HF or CV death (HR: 0.72; 95% CI: 0.66, 078; I 2: 0%) and CV death (HR: 0.82; 95% CI: 0.74, 0.91; I 2: 0%).
    Conclusions: The results of this meta-analysis confirm the growing evidence in the literature of the favourable profile of SGLT2 inhibitors in cardiovascular outcomes and mortality in patients with heart failure regardless of the baseline diabetes status. This systematic review has been registered with PROSPERO (CRD42021224777).
    DOI:  https://doi.org/10.1155/2021/9927533
  8. Int J Cardiol. 2021 Aug 26. pii: S0167-5273(21)01301-2. [Epub ahead of print]
    Sodium-glucose co-transporter-2 inhibitors eligibility in patients with heart failure with reduced ejection fraction.
    Luca Monzo, Ilaria Ferrari, Francesco Cicogna, Claudia Tota, Leonardo Calò.
       BACKGROUND: The sodium-glucose co-transporter-2 (SGLT2) inhibitors dapagliflozin and empagliflozin have been demonstrated to reduce adverse cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Limited data are available characterizing the generalizability of SGLT2 inhibitors treatment in the clinical practice. The aim of the study was to evaluate the proportion of outpatients with HFrEF that would be eligible for SGLT2 inhibitors in a contemporary real-world population.
    METHODS: We retrospectively evaluated patients with chronic stable HFrEF followed-up at the HF outpatient clinic of our institution. Patients' eligibility was assessed according to the entry criteria of DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin) trials and to US Food and Drug Administration (FDA) label criteria (only dapagliflozin).
    RESULTS: A total of 441 HFrEF patients was enrolled. According to the major inclusion and exclusion criteria from DAPA-HF and EMPEROR-Reduced trials, 198 (45%) patients would be candidates for initiation of both dapagliflozin and empagliflozin, 61 (14%) would be eligible only to dapagliflozin and 23 (5%) only to empagliflozin, without significant differences between diabetic and non-diabetic patients (p = 0.23). Among patients not suitable for gliflozins treatment (159 patients; 36%), the major determinant of ineligibility was the failure to achieve the predefined NT-proBNP inclusion threshold. Excluding NTproBNP as per FDA label criteria, dapagliflozin eligibility increased to 86%.
    CONCLUSIONS: In our real-world analysis a large proportion of HFrEF patients would be candidates for initiation of SGLT2 inhibitors, supporting its broad generalizability in clinical practice. This would be expected to reduce morbidity and mortality in eligible patients.
    Keywords:  DAPA-HF; EMPEROR-reduced; Heart failure; Sodium–glucose co-transporter inhibitor; Treatment eligibility
    DOI:  https://doi.org/10.1016/j.ijcard.2021.08.035
  9. Circulation. 2021 Aug 29.
    Effect of Empagliflozin on Worsening Heart Failure Events in Patients with Heart Failure and a Preserved Ejection Fraction: The EMPEROR-Preserved Trial.
    EMPEROR-Preserved Trial Study Group
      Background: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, but additional data are needed about its effect on inpatient and outpatient heart failure events. Methods: We randomly assigned 5988 patients with class II-IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite endpoints. Results: Empagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (432 vs 546 patients; empagliflozin vs placebo, respectively; hazard ratio 0.77, 95% CI: 0.67-0.87), P <0.0001. This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio 0.71, 95% CI 0.52-0.96, P=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio 0.73, 95% CI: 0.55-0.97,P=0.033). As compared with placebo, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 vs 610, hazard ratio 0.76, 95% CI: 0.67-0.86, P<0.0001), and patients assigned to empagliflozin were 20-50% more likely to have a better NYHA functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40-<50% and 50-<60%, but was attenuated at higher ejection fractions. Conclusions: In patients with heart failure and a preserved ejection fraction, empagliflozin produced a meaningful, early and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events. Clinical Trial Registration: The registration identifier at ClinicalTrials.gov is NCT03057977.
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.121.056824
  10. Cardiovasc Diabetol. 2021 Sep 03. 20(1): 175
    Effect of canagliflozin on N-terminal pro-brain natriuretic peptide in patients with type 2 diabetes and chronic heart failure according to baseline use of glucose-lowering agents.
    CANDLE trial investigators
       BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of a deterioration in heart failure (HF) and mortality in patients with a broad range of cardiovascular risks. Recent guidelines recommend considering the use of SGLT2 inhibitors in patients with type 2 diabetes (T2D) and HF, irrespective of their glycemic control status and background use of other glucose-lowering agents including metformin. However, only a small number of studies have investigated whether the effects of SGLT2 inhibitor in these patients differ by the concomitant use of other glucose-lowering agents.
    METHODS: This was a post-hoc analysis of the CANDLE trial (UMIN000017669), an investigator-initiated, multicenter, open-label, randomized, controlled trial. The primary aim of the analysis was to assess the effect of 24 weeks of treatment with canagliflozin, relative to glimepiride, on N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in patients with T2D and clinically stable chronic HF. In the present analysis, the effect of canagliflozin on NT-proBNP concentration was assessed in the patients according to their baseline use of other glucose-lowering agents.
    RESULTS: Almost all patients in the CANDLE trial presented as clinically stable (New York Heart Association class I to II), with about 70% of participants having HF with a preserved ejection fraction phenotype (defined as a left ventricular ejection fraction ≥ 50%) at baseline. Of the 233 patients randomized to either canagliflozin (100 mg daily) or glimepiride (starting dose 0.5 mg daily), 85 (36.5%) had not been taking any glucose-lowering agents at baseline (naïve). Of the 148 patients who had been taking at least one glucose-lowering agent at baseline (non-naïve), 44 (29.7%) and 127 (85.8%) had received metformin or a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, respectively. The group ratio (canagliflozin vs. glimepiride) of proportional changes in the geometric means of NT-proBNP concentration was 0.95 (95% confidence interval [CI] 0.76 to 1.18, p = 0.618) for the naïve subgroup, 0.92 (95% CI 0.79 to1.07, p = 0.288) for the non-naïve subgroup, 0.90 (95% CI 0.68 to 1.20, p = 0.473) for the metformin-user subgroup, and 0.91 (95% CI 0.77 to 1.08, p = 0.271) for the DPP-4 inhibitor-user subgroup. No heterogeneity in the effect of canagliflozin, relative to glimepiride, on NT-proBNP concentration was observed in the non-naïve subgroups compared to that in the naïve subgroup.
    CONCLUSION: The impact of canagliflozin treatment on NT-proBNP concentration appears to be independent of the background use of diabetes therapy in the patient population examined. Trial registration University Medical Information Network Clinical Trial Registry, number 000017669. Registered on May 25, 2015.
    Keywords:  Chronic heart failure; Dipeptidyl peptidase-4 inhibitor; Metformin; Sodium–glucose cotransporter 2 inhibitor; Type 2 diabetes
    DOI:  https://doi.org/10.1186/s12933-021-01369-5
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